Contents THe Development of QingHaosu (Artemisinin) - A View From the Outside i Foreword - Sun Manji iii Foreword - Keith Arnold vii Prefaceix ix Introd uction xxvii 1.Discovery of Qinghaosu (Artemisinin) - History of Research and Development of Artemisinin-Based Antimalarials 1 1.1 Discovery of Artemisinin and Early Antimalarial Research 3 A.The Discovery of QingHaosu(Artemisinin) 4 B.Nationwide Collaboration on Artemisinin Research in Treating Malaria 10 C.Project Validation and the National Invention Award 14 1.2 The Development of Artemisinin and ltS Derivatives as Antimalarials 14 A.Artemisinin 15 B.Artemether 18 C.Artesunate 20 D.Dihydroartemisinin 23 1.3 Innovation of Artemisinin-Based Combinations 25 A.ArtemetherLumefantrine Combination (Coartem) 25 B.Artemisinin-Naphthoquine Phosphate Combination (ARCO) 31 C.ArtemisininsPiperaquine Combinations (CV8, Artekin, Duo-Cotexin, Artequick) 34 1.4 China's Research Program Under the Chinese Steering Committee for Research of Qinghaosu and Its Derivatives 40 A.WHO Interested in CHina's Artemisinin Antimalarials 41 B.The Chinese Steering Committee for Qinghaosu Research and lts Tasks 42 C.Joint Projects Between the Chinese Steering Committee for Qinghaosu Research and WHO/TDR 44 D.Raising the Standards of New-Drug Research and Production Specifications 48 E.Surveys into Artemisia annua Linnaeus Resources and a Base for Artemisinin Production 50 F.Preparing for the Global Market 52 G.Termination of the Chinese Steering Committee for Qinghaosu ResearcH 52 1.5 Management of Artemisinin Antimalarial Projects 53 A.Clear Direction and Goals 54 B.Forward-Looking Innovation 55 C.New Centralized Management 56 D.Mutual Aid and Strength in Numbers 57 E.Respecting Knowledge and Talent 58 References 60 2.Agronomics and Biology of Artemisia annua l. 69 2.1Propagation and Cultivation of Artemisia annua 69 A.Botanical and Medicinal Properties 69 B.Resource Distribution and Origin 71 C.Propagation 73 D.Cultivation 84 2.2Cellular Engineering of Artemisia annua 90 A.Overview of Tissue and Organ Culturing 90 B.Hairy Root Cultures 92 C.induction of Shoot Clusters 93 D.Hairy Roots and Adventitious Shoots Cultured in Bioreactors 94 E.Establishment of Genetic Transformation System 95 2.3 Biosynthetic Pathways and Bioengineering of Artemisinin 99 A.Biosynthetic Pathways 99 B.Genes Involved in BiosyntHesis 102 C.Regulation of Artemisinin BiosyntHesis 106 D.Artemisinin and Precursors Synthesis in Plant Bioreactors 111 E.Combinatorial Biosynthesis of Artemisinin and Precursors in Microorganisms 112 F.Other Studies Related to Artemisinin BiosyntHesis 115 Acknowledgments 119 References 120 3.Artemisinin Chemical Research 129 3.1 Extraction and Isolation 130 A.The Yunnan Institute of Materia Medica's #120 Gasoline Extraction Method 130 B.The Institute of CHinese Materia Medica's EtHer Extraction MetHod 134 C.The Shandong Institute of CHinese Medicine's Acetone Extraction Method 135 D.TFie Guangxi Institute of Botany's and Guilin Aromatics Factory's #120 Gasoline Extraction Method 135 3.2Research Into Other Components of Artemisia annua Linnaeus 136 A.Terpenoids 136 B.Flavonoids and Coumarins 139 3.3 Physical and Spectral Characteristics of Artemisinin 139 3.4Determining the Structure of Artemisinin 140 A.Exploration of Structure via Degradation Reactions and Spectroscopic Analysis 140 B.Artemisinin Structure Determined by X-Ray Crystallography 141 3.5 Chemical Reactions of Artemisinin 147 A.Reduction of the Peroxide Group 147 B.Reduction of the Lactone Group 149 C.Acid Degradation of Artemisinin 150 D.Alkaline Degradation of Artemisinin 151 E.Pyrolysis of Artemisinin 151 3.6 Synthesis of Artemisinin 152 3.7 Quantitative Analysis of Artemisinins Compounds 156 A.Methods in the Chinese and International PHarmacopoeias 156 B.Developments in the Assay of Artemisinins in Body Fluids 161 References 167 4.Artemisinin Derivatives and Analogues 177 4.1Artemisinin Oil-Soluble Derivatives 179 4.2Artemisinin Water-Soluble Derivatives 182 4.3Artemisinin Dimeric and Trimeric Derivatives 185 4.4Artemisinin Simplified Analogues 187 4.5 Trioxaquines 189 4.6 Artemisinins Thermal Stability and Purity Analysis 190 References 192 5.Artemisinin and Derivatives: Pharmacodynamics, Toxicology, Pharmacokinetics, Mechanism of Action, Resistance, and Immune Regulation 197 5.1 Antimalarial Pharmacodynamics 198 A.Effects on the Malaria Parasite's Erythrocytic Stage 198 B.Effects of Artemisinin on Malaria Parasite's Exoerythrocytic Stage 206 C.Effect of Artemisinins on Chloroquine-Resistant Strain of Plasmodium berghei In Viv0 208 5.2 Toxicology 211 A.Studies in the 1970s 211 B.Studies in the 1980s 213 C.Trends in Toxicology ResearcH From tHe 1990s Onward 221 D.Conclusions 224 5.3 Pharmacokinetics of Artemisinin and ltS Derivatives 225 A.Artemisinin 225 B.DiFiyd roartemisinin 246 C.Artemether 252 D.Artesunate 263 5.4 Antimalarial Mechanisms of Artemisinin and ItS Derivatives 270 A.MorpHological Effects on Malaria Parasites 270 B.Effects of Artemisinins on Parasitic Biochemical Metabolism 282 C.FurtHer Research Developments in Antimalarial MecHanism of Action of Artemisinin and lts Derivatives (Artemisinins) 300 5.5 Resistance of Plasmodium falciparum to Artemisinins 311 A.Early Work in CHina and Abroad 311 B.Latest Developments in Resistance Research: Clinical and Genetic 317 5.6 Immune Regulation Effects of Artemisinin and ltS Derivatives 319 A.Nonspecific Immunity 319 B.Humoral Immunity 323 C.Cellularlmmunity 325 References 332 6.Artemisinin and Derivatives: Clinical Studies 353 6.1 Artemisinin Clinical Trials 354 A.Early Clinical Research on Oral and injectable Formulations 354 B.Artemisinin Suppositories 357 6.2Artesunate 363 A.Intravenous Artesunate 363 B.Intramuscular Artesunate in Treating Falciparum Malaria and Comparison With Piperaquine 375 C.Artesunate Tablets 379 6.3Artemether 388 A.Phase I Clinical Trial 389 B.Phase lI Clinical Trials 391 C.Phase lIl Clinical Trial of Artemether-Oil Injections 393 6.4Dihydroartemisinin Tablets 396 A.Phase I Clinical Trial 396 B.Phase Il Clinical Trials 398 C.Phase Ill Clinical Trials 401 D.Conclusion 401 6.5 Evaluation of Parasite Clearance Speeds and Exploration of Regimens 403 A.Parasite Clearance Rate and the Concepts of R Fever and T Fever, and R Coma and T Coma 403 B.Exploration of Artemisinins' Treatment Regimens 406 6.6 Artemisinins in Treating Other Parasitic Diseases 407 A.Schistosomiasis Prevention 407 B.Piroplasmosis 408 C.Paragonimiasis 409 D.Clonorchiasis 409 E.Toxoplasmosis 409 References 409 7.Artemether and Lumefantrine Tablets (Coartem) 415 7.1Lumefantrine 416 A.Chemical Synthesis 416 B.Pharmacodynamics 420 C.General Pharmacology 424 D.Toxicology 425 E.Non-Clinical Pharmacokinetics 428 F.Clinical Trials of Lumefantrine Capsules 429 7.2 Compound Artemether Tablets (Artemether-Lumefantrine Combination) 433 A.Pharmacodynamics 433 B.General Pharmacology 438 C.Toxicology 441 D.Early Clinical Trials of Compound ArtemetHer Tablets (Artemether-Lumefantrine Combination) in China 446 E.International Multicenter Clinical Trials of ArtemetHer and Lumefantrine Tablets (Coartem) 456 F.Pharmacokinetics 463 G.Effectiveness and Compliance of Artemether and Lumefantrine Tablets (Coartem) 476 Acknowledgments 477 References 477 8.Artemisinin-Naphthoquine Phosphate Combination (ARCO) 483 8.1 Naphthoquine Phosphate Research 484 A.Chemical Synthesis 484 B.Pharmacodynamics 486 C.General Pharmacology 501 D.Non-Clinical PHarmacokinetic Studies in Animals 504 E.Non-Clinical PHarmacokinetics: Action MecHanism 509 F.Toxicology 514 G.NapHthoquine PHospHate Tablets Clinical Trials 522 H.NapHthoquine PHospHate Tablets: Key Clinical Findings, Discussion, and Conclusion 535 8.2Artemisinin-Naphthoquine Phosphate Combination 538 A.Preclinical Pharmacology Studies 538 B.Clinical Trials 551 References 566 9.Artemisinins and Pyronaridine Phosphate Combination 571 9.1 Chemical Structure and Synthesis of Pyronaridine Phosphate 572 A.Designing the Chemical Structure of the New Antimalarial 572 B.SyntHesis of Pyronaridine 575 9.2 Pharmacological Studies of Pyronaridine Phosphate 576 A.The Pharmacodynamics of Pyronaridine Phosphate 576 B.Toxicology of Pyronaridine 586 9.3 Pyronaridine Clinical Trials 592 A.Efficacy on Vivax Malaria 593 B.Efficacy on Falciparum Malaria 593 C.Efficacy on Cerebral and Other Forms of Severe Malaria 596 D.Efficacy on Falciparum Malaria in Areas With Endemic Chloroquine Resistance 596 E.Efficacy on Falciparum Malaria in African Children 597 F.Efficacy on Plasmodium ovale- and Plasmodium malariae-Infected Patients 598 9.4 Combination of Artemisinin Derivatives and Pyronaridine in Treating Falciparum Malaria 598 A.Efficacy of Various Artemisinins and Pyronaridine on Falciparum Malaria 599 B.Efficacy of Dihydroartemisinin and Pyronaridine on Falciparum Malaria 600 C.Efficacy of Dihydroartemisinin and Pyronaridine on Chloroquine-Resistant Falciparum Malaria in Africa 602 References 603 10.Dihydroartemisinin and Artemisinin in Combination With Piperaquine (Artekin, Artequick); Primaquine and Malaria Transmission; and Malaria Elimination 609 10.1 Piperaquine and Piperaquine Phosphate 610 A.Synthesis of Piperaquine and Piperaquine Phosphate 610 B.Antimalarial Activity and Toxicity of Piperaquine 613 C.Pharmacokinetics of Piperaquine 621 D.Clinical Studies of Piperaquine 621 10.2 Dihydroartemisinin-Piperaquine Phosphate Tablets (Artekin) 628 A.Pharmacology and Toxicology of Dihydroartemisinin-Piperaquine Phosphate Combination (Artekin) 629 B.Artekin Clinical Trials 634 10.3 Artemisinin-Piperaquine Tablets (Artequick) 638 A.Laboratory Toxicology Studies 638 B.Allergic and Hemolytic Reactions 640 C.Clinical Trials on Artequick 640 10.4 Dihydroartemisinin-Piperaquine-Primaquine-Trimethoprim (CV8 Tablets) Clinical Trials 648 10.5 The Role of Primaquine in ACTs 653 10.6 Fast Elimination of Malaria by Source Eradication (FEMSE) Using ACTs 659 References 668 Index 671
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