Pyronaridine-Artesunate combination for the treatment of acute uncomplicated Plasmodium falciparum malaria in paediatric patients in Gabon [Elektronische Ressource] / vorgelegt von Annette Christina Schreier
Aus der Medizinischen Universitätsklinik und Poliklinik (Department) Tübingen Abteilung Innere Medizin VII Tropenmedizin (Schwerpunkt: Institut für Tropenmedizin, Reisemedizin, Humanparasitologie) Ärztlicher Direktor: Professor Dr. P. G. Kremsner Pyronaridine-Artesunate combination for the treatment of acute uncomplicated Plasmodium falciparum malaria in paediatric patients in Gabon Inaugural-Dissertation zur Erlangung des Doktorgrades der Medizin der Medizinischen Fakultät der Eberhard-Karls-Universität zu Tübingen vorgelegt von Annette Christina Schreier aus Stuttgart 2010 Dekan: Professor Dr. I. B. Autenrieth 1. Berichterstatter: Professor Dr. P. G. Kremsner 2. Berichterstatter: Professor Dr. C. Gleiter Parts of this work have already been published: Ramharter M, Kurth F, Schreier AC, et al., 2008 Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon J Infect Dis; 198(6):911-9 Table of contents Table of contents ABBREVIATIONS.............................................................................................. 1 1 INTRODUCTION ......................................................................................... 2 1.1 Malaria .......................................................................................... 2 1.1.
Aus der Medizinischen Universitätsklinik und Poliklinik (Department) Tübingen Abteilung Innere Medizin VII Tropenmedizin (Schwerpunkt: Institut für Tropenmedizin, Reisemedizin, Humanparasitologie) Ärztlicher Direktor: Professor Dr. P. G. Kremsner
Pyronaridine-Artesunate combination for the treatment of acute uncomplicated Plasmodium falciparummalaria in paediatric patients in Gabon
Inaugural-Dissertation zur Erlangung des Doktorgrades der Medizin
der Medizinischen Fakultät der Eberhard-Karls-Universität zu Tübingen
vorgelegt von Annette Christina Schreier aus Stuttgart
2010
Dekan: 1. Berichterstatter: 2. Berichterstatter:
Professor Dr. I. B. Autenrieth
Professor Dr. P. G. Kremsner Professor Dr. C. Gleiter
Parts of this work have already been published: Ramharter M, Kurth F, Schreier AC, et al., 2008 Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon J Infect Dis; 198(6):911-9
gross domestic product International Conference on Harmonization Good Clinical Practice intermittent preventive treatment in pregnant women intention to treat International Unit
late clinical failure
late parasitological failure
late treatment failure
polymerase chain reaction
parasite clearance time per protocol post treatment prophylaxis heart rate-corrected QT interval serious adverse event standard deviation sulfadoxine-pyrimethamine white blood cells World Health Organization
1
1
1.1
Introduction
Malaria
Introduction
Malaria is a widespread vector-borne infectious disease occurring in tropical and subtropical regions of Africa, Asia and South America. A significant proportion of the world’s population is affected by this fatal disease: in 2006, about 3.3 billion people worldwide were at risk of malaria and approximately 247 million malaria cases occurred, 86 % of them in African countries. The mortality due to malaria is estimated at nearly one million deaths per year, with more than 90 % occurring in Africa and 85 % being children under five years of 1 age .
1.1.1 Life cycle of Plasmodium sp. Protozoan parasites of the genusPlasmodium are the causative agent of malaria. There are several species, but only five affect humans:Plasmodium falciparum, malariae, vivax, ovaleand knowlesi.recently, Until Plasmodium knowlesi was only known as monkey malaria since it was often misdiagnosed asPlasmodium malariaehumans. Due to new molecular methods the in distinction betweenPlasmodium knowlesi andPlasmodium malariae became 2-4 evident .
Plasmodium falciparumthe most dangerous form of malaria, the so- causes calledMalaria tropica, which is almost exclusively responsible for the high mortality mentioned above. Parasites are transmitted by mosquitoes, female Anopheles spp., which ingest gametocytes during a blood meal from an infected person. Parasites pass through their sexual cycle in the guts of the mosquito and develop to sporozoites. They are transmitted by the anopheline saliva, closing the transmission cycle. After penetration of the skin sporozoites pass to the blood stream to infect liver cells. Subsequently schizonts are formed which rupture and release thousands of merozoites. They break out into the blood and infect red blood cells where they enter the erythrocytic stage of their life cycle and multiply asexually. The newly formed merozoites are released again and infect further erythrocytes. Some merozoites develop into gametocytes which