Naphthyridines

Publication Title: 
Arzneimittel-Forschung

The general pharmacological properties of YJA20379-8 (3-butyryl-4-[(R)-1-methylbenzylamino]-8-ethoxy-1,7-naphthyridine, CAS 187654-40-6), a new H+/K(+)-ATPase inhibitor with anti-ulcer activities, were investigated in mice, rats and guinea pigs. YJA20379-8 at oral doses of 25, 50 and 100 mg/kg did not affect the locomotor activity, hexobarbital hypnosis and motor coordination in mice. The drug did not have analgesic action and anticonvulsant action at the doses of 100 mg/kg p.o. The respiration and blood pressure were not affected at 10 mg/kg i.v. in rats.

Author(s): 
Lee, E. B.
Cho, S. I.
Chang, H. O.
Chang, M. S.
Kim, K. B.
Lee, S. B.
Choi, W. S.
Publication Title: 
The Journal of Infectious Diseases

BACKGROUND: The development of novel artemisinin-combination therapies suitable for the treatment of pediatric patients suffering from malaria is a research priority. The aim of this study was to investigate a novel fixed-dose pyronaridine-artesunate combination for the treatment of uncomplicated falciparum malaria in Gabonese patients 2-14 years old.

Author(s): 
Ramharter, Michael
Kurth, Florian
Schreier, Annette C.
Nemeth, Johannes
Glasenapp, Isabelle von
Bélard, Sabine
Schlie, Meike
Kammer, Judith
Koumba, Philemon Koumba
Cissé, Badara
Mordmüller, Benjamin
Lell, Bertrand
Issifou, Saadou
Oeuvray, Claude
Fleckenstein, Lawrence
Kremsner, Peter G.
Publication Title: 
Malaria Journal

BACKGROUND: Pyronaridine, a Mannich base anti-malarial with high efficacy against drug resistant Plasmodium falciparum, is currently evaluated as a fixed dose combination with artesunate for the treatment of uncomplicated malaria. In this study, the in vitro activity of pyronaridine against clinical isolates of P. falciparum from Lambaréné, Gabon, was assessed in order to obtain baseline data on its activity prior to its future use in routine therapy. Moreover, follow-up assessment on the in vitro activity of chloroquine, artesunate and quinine was performed.

Author(s): 
Kurth, Florian
Pongratz, Peter
Bélard, Sabine
Mordmüller, Benjamin
Kremsner, Peter G.
Ramharter, Michael
Publication Title: 
Malaria Journal

BACKGROUND: The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. METHODS: Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food.

Author(s): 
Tan, Beesan
Naik, Himanshu
Jang, In-Jin
Yu, Kyung-Sang
Kirsch, Lee E.
Shin, Chang-Sik
Craft, J. Carl
Fleckenstein, Lawrence
Publication Title: 
Antimicrobial Agents and Chemotherapy

Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay.

Author(s): 
Price, R. N.
Marfurt, J.
Chalfein, F.
Kenangalem, E.
Piera, K. A.
Tjitra, E.
Anstey, N. M.
Russell, B.
Publication Title: 
PloS One

BACKGROUND: New antimalarials are needed for P. vivax and P. falciparum malaria. This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria. METHODS AND FINDINGS: This phase III randomized, double-blind, non-inferiority trial included five centers across Cambodia, Thailand, India, and Indonesia. In a double-dummy design, patients (aged >3-? 60 years) with microscopically confirmed P.

Author(s): 
Poravuth, Yi
Socheat, Duong
Rueangweerayut, Ronnatrai
Uthaisin, Chirapong
Pyae Phyo, Aung
Valecha, Neena
Rao, B. H. Krishnamoorthy
Tjitra, Emiliana
Purnama, Asep
Borghini-Fuhrer, Isabelle
Duparc, Stephan
Shin, Chang-Sik
Fleckenstein, Lawrence
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Clinical studies and mathematical models predict that, to achieve malaria elimination, combination therapies will need to incorporate drugs that block the transmission of Plasmodium falciparum sexual stage parasites to mosquito vectors. Efforts to measure the activity of existing antimalarials on intraerythrocytic sexual stage gametocytes and identify transmission-blocking agents have, until now, been hindered by a lack of quantitative assays. Here, we report an experimental system using P.

Author(s): 
Adjalley, Sophie H.
Johnston, Geoffrey L.
Li, Tao
Eastman, Richard T.
Ekland, Eric H.
Eappen, Abraham G.
Richman, Adam
Sim, B. Kim Lee
Lee, Marcus C. S.
Hoffman, Stephen L.
Fidock, David A.
Publication Title: 
Malaria Journal

BACKGROUND: The aim of the present work was to assess i) ex vivo activity of pyronaridine (PND) and piperaquine (PPQ), as new components of artemisinin-based combination therapy (ACT), to define susceptibility baseline, ii) their activities compared to other partner drugs, namely monodesethylamodiaquine (MDAQ), lumefantrine (LMF), mefloquine (MQ), artesunate (AS) and dihydroartemisinin (DHA) against 181 Plasmodium falciparum isolates from African countries, India and Thailand, and iii) in vitro cross-resistance with other quinoline drugs, chloroquine (CQ) or quinine (QN).

Author(s): 
Pascual, Aurélie
Parola, Philippe
Benoit-Vical, Françoise
Simon, Fabrice
Malvy, Denis
Picot, Stéphane
Delaunay, Pascal
Basset, Didier
Maubon, Daniele
Faugere, Bernard
Menard, Guillaume
Bourgeois, Nathalie
Oeuvray, Claude
Didillon, Eric
Rogier, Christophe
Pradines, Bruno
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

A multiple dose, parallel group study was conducted to assess for a drug-drug interaction between the pyronaridine/artesunate (PA) combination antimalarial and ritonavir. Thirty-four healthy adults were randomized (1:1) to receive PA for 3 days or PA with ritonavir (100 mg twice daily for 17 days, PA administered on Days 8-10). Pharmacokinetic parameters for pyronaridine, artesunate, and its active metabolite dihydroartemisinin (DHA) were obtained after the last PA dose and for ritonavir on Days 1 and 10.

Author(s): 
Morris, Carrie A.
Lopez-Lazaro, Luis
Jung, Donald
Methaneethorn, Janthima
Duparc, Stephan
Borghini-Fuhrer, Isabelle
Pokorny, Rolf
Shin, Chang-Sik
Fleckenstein, Lawrence
Publication Title: 
The New England Journal of Medicine

BACKGROUND: Pyronaridine-artesunate is an artemisinin-based combination therapy under evaluation for the treatment of Plasmodium falciparum and P. vivax malaria. METHODS: We conducted a phase 3, open-label, multicenter, noninferiority trial that included 1271 patients between 3 and 60 years of age from Asia (81.3%) or Africa (18.7%) with microscopically confirmed, uncomplicated P. falciparum malaria. Patients underwent randomization for treatment with a fixed-dose combination of 180 mg of pyronaridine and 60 mg of artesunate or with 250 mg of mefloquine plus 100 mg of artesunate.

Author(s): 
Rueangweerayut, Ronnatrai
Phyo, Aung Pyae
Uthaisin, Chirapong
Poravuth, Yi
Binh, Tran Quang
Tinto, Halidou
Pénali, Louis K.
Valecha, Neena
Tien, Nong Thi
Abdulla, Salim
Borghini-Fuhrer, Isabelle
Duparc, Stephan
Shin, Chang-Sik
Fleckenstein, Lawrence
Pyronaridine–Artesunate Study Team

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