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piperaquine

Plasmodium falciparum phenotypic and genotypic resistance profile during the emergence of Piperaquine resistance in Northeastern Thailand

June 30, 2021 - 09:39 -- Open Access
Author(s): 
Boonyalai N, Thamnurak C, Gaywee J, et al.
Reference: 
Sci Rep. 2021 Jun 28;11(1):13419

Malaria remains a public health problem in Thailand, especially along its borders where highly mobile populations can contribute to persistent transmission. This study aimed to determine resistant genotypes and phenotypes of 112 Plasmodium falciparum isolates from patients along the Thai-Cambodia border during 2013-2015. The majority of parasites harbored a pfmdr1-Y184F mutation. A single pfmdr1 copy number had CVIET haplotype of amino acids 72-76 of pfcrt and no pfcytb mutations. All isolates had a single pfk13 point mutation (R539T, R539I, or C580Y), and increased % survival in the ring-stage survival assay (except for R539I).

NOT Open Access | Structure-switching aptamer sensors for the specific detection of piperaquine and mefloquine

March 24, 2021 - 15:06 -- NOT Open Access
Author(s): 
Coonahan ES, Yang KA, Pecic S, De Vos M, Wellems TE, Fay MP, Andersen JF, Tarning J, Long CA
Reference: 
Sci Transl Med. 2021 Mar 17;13(585):eabe1535

Tracking antimalarial drug use and efficacy is essential for monitoring the current spread of antimalarial drug resistance. However, available methods for determining tablet quality and patient drug use are often inaccessible, requiring well-equipped laboratories capable of performing liquid chromatography-mass spectrometry (LC-MS). Here, we report the development of aptamer-based fluorescent sensors for the rapid, specific detection of the antimalarial compounds piperaquine and mefloquine-two slow-clearing partner drugs in current first-line artemisinin-based combination therapies (ACTs).

NOT Open Access | In Vitro Susceptibility of Plasmodium falciparum Isolates from the China-Myanmar Border Area to Piperaquine and Association with Candidate Markers

March 13, 2021 - 16:31 -- NOT Open Access
Author(s): 
Si Y, Zeng W, Cui L, et al.
Reference: 
Antimicrob Agents Chemother. 2021 Mar 8:AAC.02305-20

Plasmodium falciparum from the Greater Mekong subregion has evolved resistance to the artemisinin-based combination therapy dihydroartemisinin and the partner drug piperaquine. To monitor the potential westward spread or independent evolution of piperaquine resistance, we evaluated the in vitro susceptibility of 120 P. falciparum isolates collected at the China-Myanmar border during 2007-2016.

Metabolic Retroversion of Piperaquine (PQ) via Hepatic CYP-mediated N-oxidation and Reduction: not an Important Contributor to the Prolonged Elimination of PQ

March 9, 2021 - 15:48 -- Open Access
Author(s): 
Xie Y, Zhang Y, Liu H, Xing J
Reference: 
Drug Metab Dispos. 2021 Mar 5:DMD-AR-2020-000306

As a partner antimalarial with an extremely long elimination half-life (~30 days), piperaquine (PQ) is mainly metabolized into a pharmacologically active N-oxide metabolite (PN1) in humans. In the present work, the metabolic retroversion of PQ and PN1, potentially associated with decreased clearance of PQ, was studied. The results showed that interconversion existed for PQ and its metabolite PN1. The N-oxidation of PQ to PN1 was mainly mediated by CYP3A4, and PN1 can rapidly reduce back to PQ via CYP/FMO enzymes. In accordance with these findings, the CYP non-selective inhibitor (1-ABT) or CYP3A4 inhibitor (ketoconazole) inhibited the N-oxidation pathway in liver microsomes (>90%), and the reduction metabolism was inhibited by 1-ABT (>90%) or methimazole (~50%).

NOT Open Access | Distribution and temporal dynamics of P. falciparum chloroquine resistance transporter mutations associated with piperaquine resistance in Northern Cambodia

February 3, 2021 - 15:27 -- NOT Open Access
Author(s): 
Shrestha B, Shah Z, Takala-Harrison S, et al.
Reference: 
J Infect Dis. 2021 Feb 2:jiab055

Newly emerged mutations within the Plasmodium falciparum chloroquine resistance transporter (PfCRT) can confer piperaquine resistance in the absence of amplified plasmepsin II (pfpm2). In this study, we estimated the prevalence of co-circulating piperaquine resistance mutations in P. falciparum isolates collected in northern Cambodia from 2009-2017.

Semi-mechanistic pharmacokinetic and pharmacodynamic modelling of piperaquine in a volunteer infection study with Plasmodium falciparum blood-stage malaria

January 21, 2021 - 15:29 -- Open Access
Author(s): 
Wattanakul T, Baker M, Mohrle J, McWhinney B, Hoglund RM, McCarthy JS, Tarning J
Reference: 
Antimicrob Agents Chemother. 2021 Jan 19:AAC.01583-20

Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that could be used to optimize the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated 1,800 blood-stage Plasmodium falciparum parasites.

Piperaquine pharmacokinetics during intermittent preventive treatment for malaria in pregnancy

December 29, 2020 - 15:37 -- Open Access
Author(s): 
Chotsiri P, Gutman J, Tarning J, et al.
Reference: 
Antimicrob Agents Chemother. 2020 Dec 23:AAC.01150-20

Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent-preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp.

Mass Drug Administration With High-Dose Ivermectin and Dihydroartemisinin-Piperaquine for Malaria Elimination in an Area of Low Transmission With High Coverage of Malaria Control Interventions: Protocol for the MASSIV Cluster Randomized Clinical Trial

November 25, 2020 - 12:10 -- Open Access
Author(s): 
Dabira ED, Soumare HM, D'Alessandro U, et al.
Reference: 
JMIR Res Protoc. 2020 Nov 19;9(11):e20904

With a decline in malaria burden, innovative interventions and tools are required to reduce malaria transmission further. Mass drug administration (MDA) of artemisinin-based combination therapy (ACT) has been identified as a potential tool to further reduce malaria transmission, where coverage of vector control interventions is already high. However, the impact is limited in time. Combining an ACT with an endectocide treatment that is able to reduce vector survival, such as ivermectin (IVM), could increase the impact of MDA and offer a new tool to reduce malaria transmission.

Defining the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood stage Plasmodium falciparum

November 18, 2020 - 12:18 -- Open Access
Author(s): 
McCarthy JS, Abd-Rahman AN, Collins KA, Marquart L, Griffin P, Kümmel A, Fuchs A, Winnips C, Mishra V, Csermak-Renner K, Jain JP, Gandhi P
Reference: 
Antimicrob Agents Chemother. 2020 Nov 16:AAC.01423-20

The spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma cipargamin concentrations.

NOT Open Access | Piperaquine exposure is altered by pregnancy, HIV and nutritional status in Ugandan women

October 7, 2020 - 15:38 -- NOT Open Access
Author(s): 
Hughes E, Imperial M, Savic RM, et al.
Reference: 
Antimicrob Agents Chemother. 2020 Oct 5:AAC.01013-20

Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations >10.3 ng/mL have been associated with reduced maternal parasitemia, placental malaria and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post-hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks.

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