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Isabelle Borghini-fuhrer - One of the best experts on this subject based on the ideXlab platform.
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Efficacy and Safety of Pyronaridine-Artesunate for the Treatment of Uncomplicated Plasmodium falciparum and Plasmodium vivax Malaria in Myanmar.
The American journal of tropical medicine and hygiene, 2020Co-Authors: Kay Thwe Han, Isabelle Borghini-fuhrer, Khin Lin, Zay Yar Han, Moe Kyaw Myint, Kyin Hla Aye, Aung Thi, Badri Thapa, Maria Dorina Bustos, Pascal RingwaldAbstract:Four single-arm, prospective, clinical studies of Pyronaridine-artesunate efficacy in uncomplicated Plasmodium falciparum or Plasmodium vivax malaria were conducted in Myanmar between 2017 and 2019. Eligible subjects were aged at least 6 years, with microscopically confirmed P. falciparum (n = 196) or P. vivax mono-infection (n = 206). Patients received Pyronaridine-artesunate once daily for 3 days with follow-up until day 42 for P. falciparum or day 28 for P. vivax. For the primary efficacy analysis, adequate clinical and parasitological response (ACPR) in the per-protocol population at day 42 for P. falciparum malaria was 100% (88/88; 95% CI: 95.9, 100) in northern Myanmar (Kachin State and northern Shan State), and 100% (101/101; 95% CI: 96.4, 100) in southern Myanmar (Tanintharyi Region and Kayin State). Plasmodium falciparum day-3 parasite clearance was observed for 96.9% (190/196) of patients. Mutations in the P. falciparum Kelch propeller domain (K13) were detected in 39.0% (69/177) of isolates: F446I (14.7% [26/177]), R561H (13.0% [23/177]), C580Y (10.2% [18/177]), and P574L (1.1% [2/177]). For P. vivax, the day-28 ACPR was 100% (104/104; 95% CI: 96.5, 100) in northern Myanmar and 100% (97/97; 95% CI: 96.3, 100) in southern Myanmar. Across both P. vivax studies, 100% (206/206) of patients had day-3 parasite clearance. There were no adverse events. Pyronaridine-artesunate had excellent efficacy in Myanmar against P. falciparum and P. vivax and was well tolerated. This study supports the inclusion of Pyronaridine-artesunate in national malaria treatment guidelines for Myanmar.
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Safety and efficacy of re-treatments with Pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial
The Lancet. Infectious diseases, 2015Co-Authors: Issaka Sagara, Isabelle Borghini-fuhrer, Abdoul Habib Beavogui, Issaka Zongo, Issiaka Soulama, Bakary Fofana, Daouda Camara, Anyirékun Fabrice Somé, Aboubacar S Coulibaly, Oumar B TraoreAbstract:Summary Background Sparse data on the safety of Pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use. We therefore compared the safety of Pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a substudy analysis. Methods This planned substudy analysis of the randomised, open-label West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) phase 3b/4 trial was done at six health facilities in Mali, Burkina Faso, and Guinea in patients (aged ≥6 months and bodyweight ≥5 kg) with uncomplicated microscopically confirmed Plasmodium spp malaria (parasite density Findings Following first treatment, 13 (1%) of 996 patients had hepatotoxicity (including one [ Interpretation The findings that Pyronaridine-artesunate safety and efficacy were similar on first malaria treatment versus re-treatment of subsequent episodes lend support for the wider access to Pyronaridine-artesunate as an alternative artemisinin-based combination treatment for malaria in sub-Saharan Africa. Funding European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), UK Medical Research Council, Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), Malaria Research and Training Centre (Bamako, Mali), Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Sante (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Sante Rurale (Republic of Guinea).
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Mass balance and metabolism of the antimalarial Pyronaridine in healthy volunteers
European Journal of Drug Metabolism and Pharmacokinetics, 2015Co-Authors: Carrie A. Morris, Stephan Duparc, Stephen R. Dueker, Peter N. Lohstroh, Li-quan Wang, Xin-ping Fang, Donald Jung, Luis Lopez-lazaro, Mark Baker, Isabelle Borghini-fuhrerAbstract:This was a single dose mass balance and metabolite characterization study of the antimalarial agent Pyronaridine. Six healthy male adults were administered a single oral dose of 720 mg Pyronaridine tetraphosphate with 800 nCi of radiolabeled ^14C-Pyronaridine. Urine and feces were continuously collected through 168 h post-dose, with intermittent 48 h collection periods thereafter through 2064 h post-dose. Drug recovery was computed for analyzed samples and interpolated for intervening time periods in which collection did not occur. Blood samples were obtained to evaluate the pharmacokinetics of total radioactivity and of the parent compound. Total radioactivity in urine, feces, and blood samples was determined by accelerator mass spectrometry (AMS); parent concentrations in blood were determined with LC/MS. Metabolite identification based on blood, urine, and feces samples was conducted using a combination of LC + AMS for identifying radiopeaks, followed by LC/MS/MS for identity confirmation/elucidation. The mean cumulative drug recovery in the urine and feces was 23.7 and 47.8 %, respectively, with an average total recovery of 71.5 %. Total radioactivity was slowly eliminated from blood, with a mean half-life of 33.5 days, substantially longer than the mean parent compound half-life of 5.03 days. Total radioactivity remained detectable in urine and feces collected in the final sampling period, suggesting ongoing elimination. Nine primary and four secondary metabolites of Pyronaridine were identified. This study revealed that Pyronaridine and its metabolites are eliminated by both the urinary and fecal routes over an extended period of time, and that multiple, varied pathways characterize Pyronaridine metabolism.
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Pharmacokinetic Interaction between Pyronaridine-Artesunate and Metoprolol
Antimicrobial agents and chemotherapy, 2014Co-Authors: Carrie A. Morris, Stephan Duparc, Sarah Arbe-barnes, Isabelle Borghini-fuhrer, Luis Lopez-lazaro, Rolf Pokorny, Robert M Miller, Jang-sik Shin, Lawrence FleckensteinAbstract:ABSTRACT The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (Pyronaridine-artesunate [PA]) and the CYP2D6 probe substrate metoprolol and to assess the safety of 60-day or 90-day PA redosing, particularly with regard to liver biochemistry parameters. Healthy adult subjects were randomized to arm A ( n = 26) or arm B ( n = 30), with the arm A subjects administered 100 mg metoprolol tartrate in the first period, 100 mg metoprolol tartrate with the third of three daily doses of PA in the second period, and three daily doses of PA alone in the 90-day redosing period. The arm B subjects received the three-day PA regimen in the first period, with redosing of the regimen after 60 days in the second period. The noncompartmental pharmacokinetic parameters were computed for metoprolol, its metabolite alpha-hydroxymetoprolol, and Pyronaridine. The coadministration of metoprolol and PA was associated with an average 47.93% (90% confidence interval [CI], 30.52, 67.66) increase in the maximum concentration of metoprolol and a 25.60% (90% CI, 15.78, 36.25) increase in the metoprolol area under the concentration-time curve from time zero to the last quantifiable concentration obtained (AUC 0- t ); these increases most likely resulted from Pyronaridine-mediated CYP2D6 inhibition. No interaction effect of metoprolol with Pyronaridine was apparent. Following dosing with PA, some subjects experienced rises in liver function tests above the upper limit of normal during the first few days following PA administration. All such elevations resolved typically within 10 days, and up to 30 days at most. In subjects who were redosed, the incidences of alanine aminotransferase (ALT) or aspartate transaminase (AST) level elevations were similar on the first and second administrations, with no marked difference between the 60-day and 90-day redosing.
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Review of Pyronaridine anti-malarial properties and product characteristics.
Malaria journal, 2012Co-Authors: Simon L. Croft, Stephan Duparc, Sarah Arbe-barnes, J. Carl Craft, Chang Sik Shin, Lawrence Fleckenstein, Isabelle Borghini-fuhrer, Han Jong RimAbstract:Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown Pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to Pyronaridine appears to emerge slowly and is further retarded when Pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for Pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined Pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.
Walther H Wernsdorfer - One of the best experts on this subject based on the ideXlab platform.
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Synergism between Pyronaridine and retinol in Plasmodium vivax in vitro
Wiener Klinische Wochenschrift, 2010Co-Authors: Julia Riedl, Gunther Wernsdorfer, Kanungnit Congpuong, Jeeraphat Sirichaisinthop, Ursula Wiedermann, Walther H WernsdorferAbstract:Estimates of the annual number of infections with Plasmodium vivax reach 391 million. So far the blood-schizontocidal therapy with chloroquine remained effective in most parts of the world, but reports about emerging resistance are increasing. The study had the objective of determining the pharmacodynamic interaction between Pyronaridine and retinol in Plasmodium vivax, since Pyronaridine is a potential alternative for chloroquine and an earlier study had shown strong synergism between Pyronaridine and retinol in Plasmodium falciparum. The study was conducted at the Malaria Clinic of Mae Sot, Tak Province, Thailand, near the border to Myanmar. The in vitro observations followed the method of Tasanor. Successful tests were performed with 44 isolates. The mean IC50, IC90 and IC99 values for Pyronaridine were 9.8, 2069.6 and 162446.5 nM. The mean IC50, IC90 and IC99 values for the combinations with retinol (corresponding to the 50th, 65th and 80th percentile of the physiological retinol levels in healthy adults) were 1.7, 542.8 and 59379.5 nM for Pyronaridine + retinol "low", for the combination with retinol "medium" they were 0.5, 313.7 and 58891.4 nM and for the combination with retinol "high" they were 0.2, 96.7 and 16754.3 nM. These results suggest strong synergism between the two substances.
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Synergism between Pyronaridine and retinol in Plasmodium vivax in vitro
Wiener klinische Wochenschrift, 2010Co-Authors: Julia Riedl, Gunther Wernsdorfer, Kanungnit Congpuong, Jeeraphat Sirichaisinthop, Ursula Wiedermann, Walther H WernsdorferAbstract:Schätzungsweise erkranken weltweit jährlich bis zu 391 Millionen Menschen an Malaria tertiana, hervorgerufen durch Plasmodium vivax . Bislang ist die blutschizontozide Therapie mit Chloroquin in weiten Teilen der Erde noch erfolgreich, doch die Berichte über Resistenzentwicklungen nehmen zu. Die Studie hatte das Ziel, die pharmakodynamische Interaktion von Pyronaridin und Retinol bei Plasmodium vivax zu untersuchen, da Untersuchungen bei Plasmodium falciparum auf hochgradigen Synergismus zwischen beiden Substanzen hinweisen und Pyronaridin eines der möglichen Ersatzmedikamente bei Eintritt von Chloroquinresistenz ist. Die Arbeiten wurden 2009 an der Malariaklinik von Mae Sot, Provinz Tak, Thailand, nahe der Grenze zu Myanmar durchgeführt. Die in-vitro Prüfungen folgten der Methode von Tasanor und ergaben für 44 Isolate erfolgreiche parallele Tests. Die mittleren IC_50, IC_90 und IC_99 Werte für Pyronaridin betrugen 9,8; 2069,6 und 162446,5 nM und konnten durch Zugabe von Retinol (entsprechend Konzentrationen der 50., 65. und 80. Perzentile der physiologischen Retinolspiegel gesunder Erwachsener) auf 1,7; 542,8 und 59379,5 nM für Pyronaridin + Retinol "low", auf 0,5; 313,7 und 58891,4 nM für Pyronaridin + Retinol "medium und auf 0,2; 96,7 und 16754,3 nM für Pyronaridin + Retinol "high" gesenkt werden. Diese Ergebnisse weisen auf starken Synergismus zwischen beiden Substanzen hin. Estimates of the annual number of infections with Plasmodium vivax reach 391 million. So far the blood-schizontocidal therapy with chloroquine remained effective in most parts of the world, but reports about emerging resistance are increasing. The study had the objective of determining the pharmacodynamic interaction between Pyronaridine and retinol in Plasmodium vivax , since Pyronaridine is a potential alternative for chloroquine and an earlier study had shown strong synergism between Pyronaridine and retinol in Plasmodium falciparum . The study was conducted at the Malaria Clinic of Mae Sot, Tak Province, Thailand, near the border to Myanmar. The in vitro observations followed the method of Tasanor. Successful tests were performed with 44 isolates. The mean IC_50, IC_90 and IC_99 values for Pyronaridine were 9.8, 2069.6 and 162446.5 nM. The mean IC_50, IC_90 and IC_99 values for the combinations with retinol (corresponding to the 50th, 65th and 80th percentile of the physiological retinol levels in healthy adults) were 1.7, 542.8 and 59379.5 nM for Pyronaridine + retinol "low", for the combination with retinol "medium" they were 0.5, 313.7 and 58891.4 nM and for the combination with retinol "high" they were 0.2, 96.7 and 16754.3 nM. These results suggest strong synergism between the two substances.
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Synergism between Pyronaridine and retinol in Plasmodium falciparum in vitro
Wiener klinische Wochenschrift, 2009Co-Authors: Pippa Proell, Gunther Wernsdorfer, Kanungnit Congpuong, Franz F. Reinthaler, Ursula Wiedermann, Walther H WernsdorferAbstract:Pyronaridine, a naphthyridine derivative and Mannich base, is a highly active blood schizontocide and currently being explored as partner in artemisinin-based combination therapy (ACT). In this study, carried out 2008 in Mae Sot, Thailand, the activity of Pyronaridine was found to be compromised, obviously as the result of mono-therapy in an adjacent area. The Pyronaridine sensitivity and the interaction between Pyronaridine and retinol at concentrations corresponding to the 50^th, 65^th and 80^th percentile of the physiological retinol levels in healthy adults were assessed in 38 fresh isolates of P. falciparum . The mean IC50, IC90 and IC99 values for Pyronaridine were 12.7, 201.4 and 3084.2 nM, those for Pyronaridine + retinol "low" 1.2, 14.0 and 102.6 nM, those for Pyronaridine + retinol "medium" 0.6, 7.4 and 54.8 nM, and those for Pyronaridine + retinol "high" 0.9, 8.2 and 47.8 nM. There was significant evidence of strong synergism between Pyronaridine and retinol against P. falciparum . Pyronaridin, eine zur Gruppe der Naphthyridine gehörige Mannich-Base, ist ein hoch wirksames Blutschizontozid, welches derzeit als möglicher Partner in der Artemisinin-basierenden Kombinationstherapie (ACT) gilt. In dieser, 2008 in Mae Sot, Thailand, durchgeführten Studie zeigte Pyronaridin erheblich reduzierte Wirkung, offenbar in Folge von freizügiger Monotherapie im Nachbarland. Die Pyronaridinempfindlichkeit und die Interaktion zwischen Pyronaridin und Retinol, letzteres in Konzentrationen entsprechend der 50., 65. und 80. Perzentile der physiologischen Retinolspiegel bei gesunden Erwachsenen, wurde bei 38 frischen Isolaten von P. falciparum ermittelt. Die mittleren IC50, IC90 und IC99 Werte für Pyronaridin waren 12,7, 201,4 bzw. 3084,2 nM, jene für Pyronaridin + Retinol "niedrig" 1,2, 14,0 bzw. 102,6 nM, jene für Pyronaridin + Retinol "mittel" 0,6, 7,4 bzw. 54,8 nM, und jene für Pyronaridin + Retinol "hoch" 0,9, 8,2 bzw. 47,8 nM. Die Ergebnisse weisen auf hochgradigen Synergismus zwischen Pyronaridin und Retinol hin.
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Synergism between Pyronaridine and retinol in Plasmodium falciparum in vitro.
Wiener klinische Wochenschrift, 2009Co-Authors: Pippa Proell, Gunther Wernsdorfer, Kanungnit Congpuong, Franz F. Reinthaler, Ursula Wiedermann, Walther H WernsdorferAbstract:Pyronaridine, a naphthyridine derivative and Mannich base, is a highly active blood schizontocide and currently being explored as partner in artemisinin-based combination therapy (ACT). In this study, carried out 2008 in Mae Sot, Thailand, the activity of Pyronaridine was found to be compromised, obviously as the result of mono-therapy in an adjacent area. The Pyronaridine sensitivity and the interaction between Pyronaridine and retinol at concentrations corresponding to the 50th, 65th and 80th percentile of the physiological retinol levels in healthy adults were assessed in 38 fresh isolates of P. falciparum. The mean IC50, IC90 and IC99 values for Pyronaridine were 12.7, 201.4 and 3084.2 nM, those for Pyronaridine + retinol "low" 1.2, 14.0 and 102.6 nM, those for Pyronaridine + retinol "medium" 0.6, 7.4 and 54.8 nM, and those for Pyronaridine + retinol "high" 0.9, 8.2 and 47.8 nM. There was significant evidence of strong synergism between Pyronaridine and retinol against P. falciparum.
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Clinical study of Pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand.
The American journal of tropical medicine and hygiene, 1996Co-Authors: Sornchai Looareesuwan, Dennis E. Kyle, Chaisin Viravan, Vanijanonta S, Polrat Wilairatana, Walther H WernsdorferAbstract:One hundred one adult patients with acute uncomplicated falciparum malaria were treated with Pyronaridine. All patients were admitted to the Bangkok Hospital for Tropical Diseases for 28 days to exclude reinfection. Sixty-nine patients (Group I) received Pyronaridine 1,200 mg over a three-day period and 32 patients (Group II) received 1,800 mg Pyronaridine over a five-day period. Cure rates for the two groups were 63% (38 of 60) for Group I and 88% (23 of 26) for Group II (P
Michael Ramharter - One of the best experts on this subject based on the ideXlab platform.
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ral ssBioMed CentMalaria Journal Open AcceResearch In
2016Co-Authors: Florian Kurth, Peter Pongratz, Sabine Bélard, Benjamin Mordmüller, Peter G. Kremsner, Michael RamharterAbstract:vitro activity of Pyronaridine against Plasmodium falciparum and comparative evaluation of anti-malarial drug susceptibility assay
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Pyronaridine artesunate granules versus artemether lumefantrine crushed tablets in children with plasmodium falciparum malaria a randomized controlled trial
Malaria Journal, 2012Co-Authors: Kassoum Kayentao, Antoinette Tshefu, Michael Ramharter, Louis K Penali, Ogobara K Doumbo, Andre Toure Offianan, K M Bhatt, Joshua Kimani, Jack KokolomamiAbstract:Background Children are most vulnerable to malaria. A Pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria.
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Pyronaridine: a new 'old' drug on the verge of entering the antimalarial armamentarium.
Expert review of anti-infective therapy, 2011Co-Authors: Florian Kurth, Sabine Bélard, Arti Basra, Michael RamharterAbstract:Evaluation of: Price RN, Marfurt J, Chalfein F et al. In vitro activity of Pyronaridine against mutidrug-resistant Plasmodium falciparum and Plasmodium vivax. Antimicrob. Agents Chemother. 54, 5146–5150 (2010).Pyronaridine–artesunate is a promising new artemisinin-based combination therapy for the treatment of uncomplicated falciparum malaria and the first systematically evaluated artemisinin-based combination therapy for vivax malaria. The 3-day regimen proved to be highly efficacious in clinical trials in Africa and Asia and is currently under review by the EMA. Price et al. report data of an in vitro drug-susceptibility study evaluating the activity of Pyronaridine against Plasmodium vivax and Plasmodium falciparum field isolates from Papua, Indonesia. The authors demonstrate high in vitro activity of Pyronaridine at low nanomolar concentrations that is only paralleled by the artemisinin class of antimalarials. Besides exciting methodological insights into the new field of in vitro drug-susceptibility ...
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In vitro activity of Pyronaridine against Plasmodium falciparum and comparative evaluation of anti-malarial drug susceptibility assays
Malaria journal, 2009Co-Authors: Florian Kurth, Peter Pongratz, Sabine Bélard, Benjamin Mordmüller, Peter G. Kremsner, Michael RamharterAbstract: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 Lambarene, 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. In vitro response of field isolates of P. falciparum to Pyronaridine, chloroquine, artesunate and quinine was assessed using the traditional WHO microtest. In addition, the histidine-rich protein 2 (HRP-2) assay was performed and evaluated for its future implementation for follow-up of drug susceptibility testing. Pyronaridine exhibited a high in vitro activity against P. falciparum, with a geometric mean cut-off concentration of 9.3 nmol/l. Fifty percent effective concentrations were 1.9 nmol/l and 2.0 nmol/l in the WHO microtest and HRP-2 assay, respectively. Results matched closely in vivo findings from a recent clinical trial on Pyronaridine-artesunate treatment. One isolate showed diminished sensitivity to artesunate. For chloroquine and quinine resistance levels were comparable to prior studies from Lambarene. Results from the novel HRP-2 assay corresponded well to those obtained by the WHO microtest. Pyronaridine is highly active in chloroquine-resistant parasites and seems a promising partner drug for artemisinin-based combination therapy in Africa.
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Fixed-Dose Pyronaridine-Artesunate Combination for Treatment of Uncomplicated Falciparum Malaria in Pediatric Patients in Gabon
The Journal of infectious diseases, 2008Co-Authors: Michael Ramharter, Florian Kurth, Sabine Bélard, Annette C. Schreier, Johannes Nemeth, Isabelle Von Glasenapp, Meike Schlie, Judith Kammer, Philemon Koumba Koumba, Badara CisseAbstract: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. The study was designed as an open-label dose-escalation study recruiting 60 pediatric patients sequentially in 4 treatment cohorts: study drugs were administered once daily for 3 days as tablet coformulations (Pyronaridine: artesunate ratios of 6:2 9:3 and 12:4 mg/kg) and as a granule coformulation (Pyronaridine:artesunate ratio of 9:3 mg/kg). The primary end points were tolerability safety and pharmacokinetics of Pyronaridine-artesunate treatment. Efficacy was treated as a secondary outcome measure. The drugs had a good tolerability and safety profile at all dose levels. Pharmacokinetic analysis revealed a dose-dependent increase in the maximum plasma/blood concentration and the area under the curve as well as comparable relative bioavailability for the granule coformulation. Polymerase chain reaction-corrected cure rates at day 28 were 100% in per-protocol analysis at all dose levels. Pyronaridine-artesunate is a promising novel artemisinin-combination therapy for pediatric patients with uncomplicated Plasmodium falciparum malaria and the development of both the tablet and the granule coformulations is warranted. (authors)
Lawrence Fleckenstein - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic Interaction between Pyronaridine-Artesunate and Metoprolol
Antimicrobial agents and chemotherapy, 2014Co-Authors: Carrie A. Morris, Stephan Duparc, Sarah Arbe-barnes, Isabelle Borghini-fuhrer, Luis Lopez-lazaro, Rolf Pokorny, Robert M Miller, Jang-sik Shin, Lawrence FleckensteinAbstract:ABSTRACT The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (Pyronaridine-artesunate [PA]) and the CYP2D6 probe substrate metoprolol and to assess the safety of 60-day or 90-day PA redosing, particularly with regard to liver biochemistry parameters. Healthy adult subjects were randomized to arm A ( n = 26) or arm B ( n = 30), with the arm A subjects administered 100 mg metoprolol tartrate in the first period, 100 mg metoprolol tartrate with the third of three daily doses of PA in the second period, and three daily doses of PA alone in the 90-day redosing period. The arm B subjects received the three-day PA regimen in the first period, with redosing of the regimen after 60 days in the second period. The noncompartmental pharmacokinetic parameters were computed for metoprolol, its metabolite alpha-hydroxymetoprolol, and Pyronaridine. The coadministration of metoprolol and PA was associated with an average 47.93% (90% confidence interval [CI], 30.52, 67.66) increase in the maximum concentration of metoprolol and a 25.60% (90% CI, 15.78, 36.25) increase in the metoprolol area under the concentration-time curve from time zero to the last quantifiable concentration obtained (AUC 0- t ); these increases most likely resulted from Pyronaridine-mediated CYP2D6 inhibition. No interaction effect of metoprolol with Pyronaridine was apparent. Following dosing with PA, some subjects experienced rises in liver function tests above the upper limit of normal during the first few days following PA administration. All such elevations resolved typically within 10 days, and up to 30 days at most. In subjects who were redosed, the incidences of alanine aminotransferase (ALT) or aspartate transaminase (AST) level elevations were similar on the first and second administrations, with no marked difference between the 60-day and 90-day redosing.
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safety and efficacy of Pyronaridine artesunate in uncomplicated acute malaria an integrated analysis of individual patient data from six randomized clinical trials
Malaria Journal, 2013Co-Authors: Stephan Duparc, Chang Sik Shin, Isabelle Borghinifuhrer, Carl J Craft, Sarah Arbebarnes, Robert M Miller, Lawrence FleckensteinAbstract:Background Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.
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Review of Pyronaridine anti-malarial properties and product characteristics.
Malaria journal, 2012Co-Authors: Simon L. Croft, Stephan Duparc, Sarah Arbe-barnes, J. Carl Craft, Chang Sik Shin, Lawrence Fleckenstein, Isabelle Borghini-fuhrer, Han Jong RimAbstract:Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown Pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to Pyronaridine appears to emerge slowly and is further retarded when Pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for Pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined Pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.
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Drug-drug interaction analysis of Pyronaridine/artesunate and ritonavir in healthy volunteers.
The American journal of tropical medicine and hygiene, 2012Co-Authors: Carrie A. Morris, Janthima Methaneethorn, Stephan Duparc, Chang Sik Shin, Isabelle Borghini-fuhrer, Donald Jung, Luis Lopez-lazaro, Rolf Pokorny, Lawrence FleckensteinAbstract: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. Ritonavir coadministration did not markedly change Pyronaridine pharmacokinetics but resulted in a 27% increase in artesunate area under the curve (AUC) and a 38% decrease in DHA AUC. Ritonavir exposure was increased 3.2-fold in the presence of PA. The only relevant safety observations were increases in liver enzymes, only reaching a clinically significant grade in the PA + ritonavir arm. It was concluded that coadministered ritonavir and PA interact to alter exposure to artesunate, DHA, and ritonavir itself.
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drug drug interaction analysis of Pyronaridine artesunate and ritonavir in healthy volunteers
American Journal of Tropical Medicine and Hygiene, 2012Co-Authors: Carrie A. Morris, Janthima Methaneethorn, Stephan Duparc, Chang Sik Shin, Isabelle Borghinifuhrer, Donald Jung, Rolf Pokorny, Luis Lopezlazaro, Lawrence FleckensteinAbstract: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. Ritonavir coadministration did not markedly change Pyronaridine pharmacokinetics but resulted in a 27% increase in artesunate area under the curve (AUC) and a 38% decrease in DHA AUC. Ritonavir exposure was increased 3.2-fold in the presence of PA. The only relevant safety observations were increases in liver enzymes, only reaching a clinically significant grade in the PA + ritonavir arm. It was concluded that coadministered ritonavir and PA interact to alter exposure to artesunate, DHA, and ritonavir itself.
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Mass balance and metabolism of the antimalarial Pyronaridine in healthy volunteers
European Journal of Drug Metabolism and Pharmacokinetics, 2015Co-Authors: Carrie A. Morris, Stephan Duparc, Stephen R. Dueker, Peter N. Lohstroh, Li-quan Wang, Xin-ping Fang, Donald Jung, Luis Lopez-lazaro, Mark Baker, Isabelle Borghini-fuhrerAbstract:This was a single dose mass balance and metabolite characterization study of the antimalarial agent Pyronaridine. Six healthy male adults were administered a single oral dose of 720 mg Pyronaridine tetraphosphate with 800 nCi of radiolabeled ^14C-Pyronaridine. Urine and feces were continuously collected through 168 h post-dose, with intermittent 48 h collection periods thereafter through 2064 h post-dose. Drug recovery was computed for analyzed samples and interpolated for intervening time periods in which collection did not occur. Blood samples were obtained to evaluate the pharmacokinetics of total radioactivity and of the parent compound. Total radioactivity in urine, feces, and blood samples was determined by accelerator mass spectrometry (AMS); parent concentrations in blood were determined with LC/MS. Metabolite identification based on blood, urine, and feces samples was conducted using a combination of LC + AMS for identifying radiopeaks, followed by LC/MS/MS for identity confirmation/elucidation. The mean cumulative drug recovery in the urine and feces was 23.7 and 47.8 %, respectively, with an average total recovery of 71.5 %. Total radioactivity was slowly eliminated from blood, with a mean half-life of 33.5 days, substantially longer than the mean parent compound half-life of 5.03 days. Total radioactivity remained detectable in urine and feces collected in the final sampling period, suggesting ongoing elimination. Nine primary and four secondary metabolites of Pyronaridine were identified. This study revealed that Pyronaridine and its metabolites are eliminated by both the urinary and fecal routes over an extended period of time, and that multiple, varied pathways characterize Pyronaridine metabolism.
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Pharmacokinetic Interaction between Pyronaridine-Artesunate and Metoprolol
Antimicrobial agents and chemotherapy, 2014Co-Authors: Carrie A. Morris, Stephan Duparc, Sarah Arbe-barnes, Isabelle Borghini-fuhrer, Luis Lopez-lazaro, Rolf Pokorny, Robert M Miller, Jang-sik Shin, Lawrence FleckensteinAbstract:ABSTRACT The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (Pyronaridine-artesunate [PA]) and the CYP2D6 probe substrate metoprolol and to assess the safety of 60-day or 90-day PA redosing, particularly with regard to liver biochemistry parameters. Healthy adult subjects were randomized to arm A ( n = 26) or arm B ( n = 30), with the arm A subjects administered 100 mg metoprolol tartrate in the first period, 100 mg metoprolol tartrate with the third of three daily doses of PA in the second period, and three daily doses of PA alone in the 90-day redosing period. The arm B subjects received the three-day PA regimen in the first period, with redosing of the regimen after 60 days in the second period. The noncompartmental pharmacokinetic parameters were computed for metoprolol, its metabolite alpha-hydroxymetoprolol, and Pyronaridine. The coadministration of metoprolol and PA was associated with an average 47.93% (90% confidence interval [CI], 30.52, 67.66) increase in the maximum concentration of metoprolol and a 25.60% (90% CI, 15.78, 36.25) increase in the metoprolol area under the concentration-time curve from time zero to the last quantifiable concentration obtained (AUC 0- t ); these increases most likely resulted from Pyronaridine-mediated CYP2D6 inhibition. No interaction effect of metoprolol with Pyronaridine was apparent. Following dosing with PA, some subjects experienced rises in liver function tests above the upper limit of normal during the first few days following PA administration. All such elevations resolved typically within 10 days, and up to 30 days at most. In subjects who were redosed, the incidences of alanine aminotransferase (ALT) or aspartate transaminase (AST) level elevations were similar on the first and second administrations, with no marked difference between the 60-day and 90-day redosing.
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safety and efficacy of Pyronaridine artesunate in uncomplicated acute malaria an integrated analysis of individual patient data from six randomized clinical trials
Malaria Journal, 2013Co-Authors: Stephan Duparc, Chang Sik Shin, Isabelle Borghinifuhrer, Carl J Craft, Sarah Arbebarnes, Robert M Miller, Lawrence FleckensteinAbstract:Background Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.
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Review of Pyronaridine anti-malarial properties and product characteristics.
Malaria journal, 2012Co-Authors: Simon L. Croft, Stephan Duparc, Sarah Arbe-barnes, J. Carl Craft, Chang Sik Shin, Lawrence Fleckenstein, Isabelle Borghini-fuhrer, Han Jong RimAbstract:Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown Pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to Pyronaridine appears to emerge slowly and is further retarded when Pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for Pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined Pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.
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Drug-drug interaction analysis of Pyronaridine/artesunate and ritonavir in healthy volunteers.
The American journal of tropical medicine and hygiene, 2012Co-Authors: Carrie A. Morris, Janthima Methaneethorn, Stephan Duparc, Chang Sik Shin, Isabelle Borghini-fuhrer, Donald Jung, Luis Lopez-lazaro, Rolf Pokorny, Lawrence FleckensteinAbstract: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. Ritonavir coadministration did not markedly change Pyronaridine pharmacokinetics but resulted in a 27% increase in artesunate area under the curve (AUC) and a 38% decrease in DHA AUC. Ritonavir exposure was increased 3.2-fold in the presence of PA. The only relevant safety observations were increases in liver enzymes, only reaching a clinically significant grade in the PA + ritonavir arm. It was concluded that coadministered ritonavir and PA interact to alter exposure to artesunate, DHA, and ritonavir itself.
