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The Development of Qinghaosu (Artemisinin) - A View From the Outside Foreword - Sun Manji Foreword - Keith Arnold Preface Introduction 1.Discovery of Qinghaosu (Artemisinin)--History of Research and Develoment of Artemisinin-Based Antimalarials 1.1 Discovery of Artemisinin and Early Antimalarial Research A.The Discovery of Qinghaosu(Artemisinin) B.Nationwide Collaboration on Artemisinin Research in Treating Malaria C.Project Validation and the National Invention Award 1.2 The Development of Artemisinin and Its Derivatives asAntimalarials A.Artemisinin B.Artemether C.Artesunate D.Dihydroartemisinin 1.3 Innovation of Artemisinin-Based Combinations A.Artemether-Lumefantrine Combination (Coartem) B.Artemisinin-Naphthoquine Phosphate Combination (ARCO) C.Artemisinins-Piperaquine Combinations (CV8, Artekin,Duo-Cotexin, Artequick) 1.4 China's Research Program Under the Chinese Steering Committee for Research of Qinghaosu and Its Derivatives A.WHO Interested in China's Artemisinin Antimalarials B.The Chinese Steering Committee for Qinghaosu Research and Its Tasks C.Joint Projects Between the Chinese Steering Committee for Qinghaosu Research and WHO/TDR D.Raising the Standards of New-Drug Research and Production Specifications E.Surveys into Artemisia annua Linnaeus Resources and a Base for Artemisinin Production F.Preparing for the Global Market G.Termination of the Chinese Steering Committee for Qinghaosu Research 1.5 Management of Artemisinin Antimalarial Projects A.Clear Direction and Goals B.Forward-Looking Innovation C.New Centralized Management D.Mutual Aid and Strength in Numbers E.Respecting Knowledge and Talent References 2.Agronomics and Biology of Artemisia annua L. 2.1 Propagation and Cultivation ofArtemisia annua A.Botanical and Medicinal Properties B.Resource Distribution and Origin C.Propagation D.Cultivation 2.2 Cellular Engineering ofArtemisia annua A.Overview of Tissue and Organ Culturing B.Hairy Root Cultures C.Induction of Shoot Clusters D.Hairy Roots and Adventitious Shoots Cultured in Bioreactors E.Establishment of Genetic Transformation System 2.3 Biosynthetic Pathways and Bioengineering of Artemisinin A.Biosynthetic Pathways B.Genes Involved in Biosynthesis C.Regulation of Artemisinin Biosynthesis D.Artemisinin and Precursors Synthesis in Plant Bioreactors E.Combinatorial Biosynthesis of Artemisinin and Precursors in Microorganisms F.Other Studies Related to Artemisinin Biosynthesis Acknowledgments References 3.Artemisinin Chemical Research 3.1 Extraction and Isolation A.The Yunnan Institute of Materia Medica's #120 Gasoline Extraction Method B.The Institute of Chinese Materia Medica's Ether Extraction Method C.The Shandong Institute of Chinese Medicine's Acetone Extraction Method D.The Guangxi Institute of Botany's and Guilin Aromatics Factory's #120 Gasoline Extraction Method 3.2 Research Into Other Components of Artemisia annua Linnaeus A.Terpenoids B.Flavonoids and Coumarins 3.3 Physical and Spectral Characteristics of Artemisinin 3.4 Determining the Structure of Artemisinin A.Exploration of Structure via Degradation Reactions and Spectroscopic Analysis B.Artemisinin Structure Determined by X-Ray Crystallography 3.5 Chemical Reactions of Artemisinin A.Reduction of the Peroxide Group B.Reduction of the Lactone Group C.Acid Degradation of Artemisinin D.Alkaline Degradation of Artemisinin E.Pyrolysis of Artemisinin 3.6 Synthesis of Artemisinin 3.7 Quantitative Analysis of Artemisinins Compounds A.Methods in the Chinese and International Pharmacopoeias B.Developments in the Assay of Artemisinins in Body Fluids References 4.Artemisinin Derivatives and Analogues 4.1 Artemisinin Oil-Soluble Derivatives 4.2 Artemisinin Water-Soluble Derivatives 4.3 Artemisinin Dimeric and Trimeric Derivatives 4.4 Artemisinin Simplified Analogues 4.5 Trioxaquines 4.6 Artemisinins Thermal Stability and Purity Analysis References 5.Artemisinin and Derivatives: Pharmacodynamics,Toxicology, Pharmacokinetics, Mechanism of Action,Resistance, and Immune Regulation 5.1 Antimalarial Pharmacodynamics A.Effects on the Malaria Parasite's Erythrocytic Stage B.Effects of Artemisinin on Malaria Parasite's Exoerythrocytic Stage C.Effect of Artemisinins on Chloroquine-Resistant Strain of Plasmodium berghei ln Vivo 5.2 Toxicology A.Studies in the 1970s B.Studies in the 1980s C.Trends in Toxicology Research From the 1990s Onward D.Conclusions 5.3 Pharmacokinetics of Artemisinin and Its Derivatives A.Artemisinin B.Dihydroartemisinin C.Artemether D.Artesunate 5.4 Antimalarial Mechanisms of Artemisinin and Its Derivatives A.Morphological Effects on Malaria Parasites B.Effects of Artemisinins on Parasitic Biochemical Metabolism C.Further Research Developments in Antimalarial Mechanism of Action of Artemisinin and Its Derivatives (Artemisinins) 5.5 Resistance of Plasmodium falciparum to Artemisinins A.Early Work in China and Abroad B.Latest Developments in Resistance Research: Clinical and Genetic 5.6 Immune Regulation Effects of Artemisinin and Its Derivatives A.Nonspecific Immunity B.Humoral Immunity C.Cellular Immunity References 6.Arternisinin and Derivatives: Clinical Studies 6.1 Artemisinin Clinical Trials A.Early Clinical Research on Oral and Injectable Formulations B.Artemisinin Suppositories 6.2 Artesunate A.Intravenous Artesunate B.Intramuscular Artesunate in Treating Falciparum Malaria and Comparison With Piperaquine C.Artesunate Tablets 6.3 Artemether A.Phase I Clinical Trial B.Phase II Clinical Trials C.Phase Ill Clinical Trial of Artemether-Oil Injections 6.4 Dihydroartemisinin Tablets A.Phase I Clinical Trial B.Phase II Clinical Trials C.Phase III Clinical Trials D.Conclusion 6.5 Evaluation of Parasite Clearance Speeds and Exploration of Regimens A.Parasite Clearance Rate and the Concepts of R Fever and T Fever, and R Coma and T Coma B.Exploration of Artemisinins' Treatment Regimens 6.6 Artemisinins in Treating Other Parasitic Diseases A.Schistosomiasis Prevention B.Piroplasmosis C.Paragonimiasis D.Clonorchiasis E.Toxoplasmosis References 7.Artemether and Lumefantrine Tablets (Coartem) 7.1 Lumefantrine A.Chemical Synthesis B.Pharmacodynamics C.General Pharmacology D.Toxicology E.Non-Clinical Pharmacokinetics F.Clinical Trials of Lumefantrine Capsules 7.2 Compound Artemether Tablets (Artemether-Lumefantrine Combination) A.Pharmacodynamics B.General Pharmacology C.Toxicology D.Early Clinical Trials of Compound Artemether Tablets(Artemether-Lumefantrine Combination) in China E.International Multicenter Clinical Trials of Artemether and Lumefantrine Tablets (Coartem) F.Pharmacokinetics G. Effectiveness and Compliance of Artemether and Lumefantrine Tablets (Coartem) Acknowledgments References 8.Artemisinin-Naphthoquine Phosphate Combination (ARCO) 8.1 Naphthoquine Phosphate Research A.Chemical Synthesis B.Pharmacodynamics C.General Pharmacology D.Non-Clinical Pharmacokinetic Studies in Animals E.Non-Clinical Pharmacokinetics: Action Mechanism F.Toxicology G.Naphthoquine Phosphate Tablets Clinical Trials H.Naphthoquine Phosphate Tablets: Key Clinical Findings,Discussion, and Conclusion 8.2 Artemisinin-Naphthoquine Phosphate Combination A.Preclinical Pharmacology Studies B.Clinical Trials References 9.Artemisinins and Pyronaridine Phosphate Combination 9.1 Chemical Structure and Synthesis of Pyronaridine Phosphate A.Designing the Chemical Structure of the New Antimalarial B.Synthesis of Pyronaridine 9.2 Pharmacological Studies of Pyronaridine Phosphate A.The Pharmacodynamics of Pyronaridine Phosphate B.Toxicology of Pyronaridine 9.3 Pyronaridine Clinical Trials A.Efficacy on Vivax Malaria B.Efficacy on Falciparum Malaria C.Efficacy on Cerebral and Other Forms of Severe Malaria D.Efficacy on Falciparum Malaria in Areas With Endemic Chloroquine Resistance E.Efficacy on Falciparum Malaria in African Children F.Efficacy on Plasmodium ovale- and Plasmodium malariae-Infected Patients 9.4 Combination of Artemisinin Derivatives and Pyronaridine in Treating Falciparum Malaria A.Efficacy of Various Artemisinins and Pyronaridine on Falciparum Malaria B.Efficacy of Dihydroartemisinin and Pyronaridine on Falciparum Malaria C.Efficacy of Dihydroartemisinin and Pyronaridine on Chloroquine-Resistant Falciparum Malaria in Africa References 10.Dihydroartemisinin and Artemisinin in Combination With Piperaquine (Artekin, Artequick); Primaquine and Malaria Transmission; and Malaria Elimination 10.1 Piperaquine and Piperaquine Phosphate A.Synthesis of Piperaquine and Piperaquine Phosphate B.Antimalarial Activity and Toxicity of Piperaquine C.Pharmacokinetics of Piperaquine D.Clinical Studies of Piperaquine 10.2 Dihydroartemisinin-Piperaquine Phosphate Tablets (Artekin) A.Pharmacology and Toxicology of Dihydroartemisinin-Piperaquine Phosphate Combination (Artekin) B.Artekin Clinical Trials 10.3 Artemisinin-Piperaquine Tablets (Artequick) A.Laboratory Toxicology Studies B.Allergic and Hemolytic Reactions C.Clinical Trials on Artequick 10.4 Dihydroartemisinin-Piperaquine-Primaquine-Trimethoprim(CV8 Tablets) Clinical Trials 10.5 The Role of Primaquine in ACTs 10.6 Fast Elimination of Malaria by Source Eradication (FEMSE) Using ACTs References