Artemisinin-Based and Other Antimalarials: Detailed Account of Studies by Chinese Scientists Who Discovered and Developed Them provides a historical and scientific background of the discovery and development of artemisinin, artemisinin derivatives, combination drugs and related chemicals. It is a historical document, a scientific treatise, and a fascinating description of innovative research on new drug development that is carried out under extremely difficult conditions. The book also includes detailed experiments, physical-chemical procedures, practical methodologies and clinical trials. It is a valuable reference for students and researchers in the fields of scientific history, medicine, pharmaceutical science, chemistry, pharmacology and toxicology.
1. Introduction - p. xxvii 2. Chapter 1. Discovery of Qinghaosu (Artemisinin)—History of Research and Development of Artemisinin-Based Antimalarials - p. 1 3. 1.1. Discovery of Artemisinin and Early Antimalarial Research - p. 3 4. A. The Discovery of Qinghaosu (Artemisinin) - p. 4 5. B. Nationwide Collaboration on Artemisinin Research in Treating Malaria - p. 10 6. C. Project Validation and the National Invention Award - p. 14 7. Acknowledgments - p. 14 8. 1.2. The Development of Artemisinin and Its Derivatives as Antimalarials - p. 14 9. A. Artemisinin - p. 15 10. B. Artemether - p. 18 11. Acknowledgments - p. 20 12. C. Artesunate - p. 20 13. D. Dihydroartemisinin - p. 23 14. Acknowledgments - p. 24 15. 1.3. Innovation of Artemisinin-Based Combinations - p. 25 16. A. Artemether–Lumefantrine Combination (Coartem) - p. 25 17. Acknowledgments - p. 31 18. B. Artemisinin–Naphthoquine Phosphate Combination (ARCO) - p. 31 19. C. Artemisinins–Piperaquine Combinations (CV8, Artekin, Duo-Cotexin, Artequick) - p. 34 20. 1.4. China’s Research Program Under the Chinese Steering Committee for Research of Qinghaosu and Its Derivatives - p. 40 21. A. WHO Interest in China’s Artemisinin Antimalarials - p. 41 22. B. The Chinese Steering Committee for Qinghaosu Research and Its Tasks - p. 42 23. C. Joint Projects Between the Chinese Steering Committee for Qinghaosu Research and WHO/TDR - p. 44 24. D. Raising the Standards of New-Drug Research and Production Specifications - p. 48 25. E. Surveys into Artemisia annua Linnaeus Resources and a Base for Artemisinin Production - p. 50 26. F. Preparing for the Global Market - p. 52 27. G. Termination of the Chinese Steering Committee for Qinghaosu Research - p. 52 28. 1.5. Management of Artemisinin Antimalarial Projects - p. 53 29. A. Clear Direction and Goals - p. 54 30. B. Forward-Looking Innovation - p. 55 31. C. New Centralized Management - p. 56 32. D. Mutual Aid and Strength in Numbers - p. 57 33. E. Respecting Knowledge and Talent - p. 58 34. Chapter 2. Agronomics and Biology of Artemisia annua L. - p. 69 35. 2.1. Propagation and Cultivation of Artemisia annua - p. 69 36. A. Botanical and Medicinal Properties - p. 69 37. B. Resource Distribution and Origin - p. 71 38. C. Propagation - p. 73 39. D. Cultivation - p. 84 40. 2.2. Cellular Engineering of Artemisia annua - p. 90 41. A. Overview of Tissue and Organ Culturing - p. 90 42. B. Hairy Root Cultures - p. 92 43. C. Induction of Shoot Clusters - p. 93 44. D. Hairy Roots and Adventitious Shoots Cultured in Bioreactors - p. 94 45. E. Establishment of Genetic Transformation System - p. 95 46. Acknowledgments - p. 98 47. 2.3. Biosynthetic Pathways and Bioengineering of Artemisinin - p. 99 48. A. Biosynthetic Pathways - p. 99 49. B. Genes Involved in Biosynthesis - p. 102 50. C. Regulation of Artemisinin Biosynthesis - p. 106 51. D. Artemisinin and Precursors Synthesis in Plant Bioreactors - p. 111 52. E. Combinatorial Biosynthesis of Artemisinin and Precursors in Microorganisms - p. 112 53. F. Other Studies Related to Artemisinin Biosynthesis - p. 115 54. Chapter 3. Artemisinin Chemical Research - p. 129 55. Chapter 4. Artemisinin Derivatives and Analogues - p. 177 56. Chapter 5. Artemisinin and Derivatives: Pharmacodynamics, Toxicology, Pharmacokinetics, Mechanism of Action, Resistance, and Immune Regulation - p. 197 57. 5.1. Antimalarial Pharmacodynamics - p. 198 58. A. Effects on the Malaria Parasite’s Erythrocytic Stage - p. 198 59. B. Effects of Artemisinin on Malaria Parasite’s Exoerythrocytic Stage - p. 206 60. C. Effect of Artemisinins on Chloroquine-Resistant Strain of Plasmodium berghei In Vivo - p. 208 61. 5.2. Toxicology - p. 211 62. A. Studies in the 1970s - p. 211 63. B. Studies in the 1980s - p. 213 64. C. Trends in Toxicology Research From the 1990s Onward - p. 221 65. D. Conclusions - p. 224 66. Acknowledgments - p. 224 67. 5.3. Pharmacokinetics of Artemisinin and Its Derivatives - p. 225 68. A. Artemisinin - p. 225 69. B. Dihydroartemisinin - p. 246 70. C. Artemether - p. 252 71. D. Artesunate - p. 263 72. Acknowledgments - p. 270 73. 5.4. Antimalarial Mechanisms of Artemisinin and Its Derivatives - p. 270 74. A. Morphological Effects on Malaria Parasites - p. 270 75. B. Effects of Artemisinins on Parasitic Biochemical Metabolism - p. 282 76. C. Further Research Developments in Antimalarial Mechanism of Action of Artemisinin and Its Derivatives (Artemisinins) - p. 300 77. 5.5. Resistance of Plasmodium falciparum to Artemisinins - p. 311 78. B. Latest Developments in Resistance Research: Clinical and Genetic - p. 317 79. 5.6. Immune Regulation Effects of Artemisinin and Its Derivatives - p. 319 80. A. Nonspecific Immunity - p. 319 81. B. Humoral Immunity - p. 323 82. C. Cellular Immunity - p. 325 83. Chapter 6. Artemisinin and Derivatives: Clinical Studies - p. 353 84. 6.1. Artemisinin Clinical Trials - p. 354 85. A. Early Clinical Research on Oral and Injectable Formulations - p. 354 86. B. Artemisinin Suppositories - p. 357 87. 6.2. Artesunate - p. 363 88. A. Intravenous Artesunate - p. 363 89. B. Intramuscular Artesunate in Treating Falciparum Malaria and Comparison With Piperaquine - p. 375 90. C. Artesunate Tablets - p. 379 91. 6.3. Artemether - p. 388 92. A. Phase I Clinical Trial - p. 389 93. B. Phase II Clinical Trials - p. 391 94. C. Phase III Clinical Trial of Artemether-Oil Injections - p. 393 95. 6.4. Dihydroartemisinin Tablets - p. 396 96. A. Phase I Clinical Trial - p. 396 97. B. Phase II Clinical Trials - p. 398 98. C. Phase III Clinical Trials - p. 401 99. D. Conclusion - p. 401 100. 6.5. Evaluation of Parasite Clearance Speeds and Exploration of Regimens - p. 403 101. A. Parasite Clearance Rate and the Concepts of R Fever and T Fever, and R Coma and T Coma - p. 403 102. B. Exploration of Artemisinins’ Treatment Regimens - p. 406 103. 6.6. Artemisinins in Treating Other Parasitic Diseases - p. 407 104. A. Schistosomiasis Prevention - p. 407 105. B. Piroplasmosis - p. 408 106. C. Paragonimiasis - p. 409 107. D. Clonorchiasis - p. 409 108. E. Toxoplasmosis - p. 409 109. Chapter 7. Artemether and Lumefantrine Tablets (Coartem) - p. 415 110. 7.1. Lumefantrine - p. 416 111. 7.2. Compound Artemether Tablets (Artemether–Lumefantrine Combination) - p. 433 112. Chapter 8. Artemisinin–Naphthoquine Phosphate Combination (ARCO) - p. 483 113. 8.1. Naphthoquine Phosphate Research - p. 484 114. B. Pharmacodynamics - p. 486 115. C. General Pharmacology - p. 501 116. D. Non-Clinical Pharmacokinetic Studies in Animals - p. 504 117. E. Non-Clinical Pharmacokinetics: Action Mechanism - p. 509 118. F. Toxicology - p. 514 119. G. Naphthoquine Phosphate Tablets Clinical Trials - p. 522 120. H. Naphthoquine Phosphate Tablets: Key Clinical Findings, Discussion, and Conclusion - p. 535 121. 8.2. Artemisinin–Naphthoquine Phosphate Combination - p. 538 122. A. Preclinical Pharmacology Studies - p. 538 123. B. Clinical Trials - p. 551 124. Chapter 9. Artemisinins and Pyronaridine Phosphate Combination - p. 571 125. Chapter 10. Dihydroartemisinin and Artemisinin in Combination With Piperaquine (Artekin, Artequick); Primaquine and Malaria Transmission; and Malaria Elimination - p. 609 126. Index - p. 671
Artemisinin-Based and Other Antimalarials: Detailed Account of Studies by Chinese Scientists Who Discovered and Developed Them provides a historical and scientific background of the discovery and development of artemisinin, artemisinin derivatives, combination drugs and related chemicals. It is a historical document, a scientific treatise, and a fascinating description of innovative research on new drug development that is carried out under extremely difficult conditions. The book also includes detailed experiments, physical-chemical procedures, practical methodologies and clinical trials. It is a valuable reference for students and researchers in the fields of scientific history, medicine, pharmaceutical science, chemistry, pharmacology and toxicology.
1. Introduction - p. xxvii 2. Chapter 1. Discovery of Qinghaosu (Artemisinin)—History of Research and Development of Artemisinin-Based Antimalarials - p. 1 3. 1.1. Discovery of Artemisinin and Early Antimalarial Research - p. 3 4. A. The Discovery of Qinghaosu (Artemisinin) - p. 4 5. B. Nationwide Collaboration on Artemisinin Research in Treating Malaria - p. 10 6. C. Project Validation and the National Invention Award - p. 14 7. Acknowledgments - p. 14 8. 1.2. The Development of Artemisinin and Its Derivatives as Antimalarials - p. 14 9. A. Artemisinin - p. 15 10. B. Artemether - p. 18 11. Acknowledgments - p. 20 12. C. Artesunate - p. 20 13. D. Dihydroartemisinin - p. 23 14. Acknowledgments - p. 24 15. 1.3. Innovation of Artemisinin-Based Combinations - p. 25 16. A. Artemether–Lumefantrine Combination (Coartem) - p. 25 17. Acknowledgments - p. 31 18. B. Artemisinin–Naphthoquine Phosphate Combination (ARCO) - p. 31 19. C. Artemisinins–Piperaquine Combinations (CV8, Artekin, Duo-Cotexin, Artequick) - p. 34 20. 1.4. China’s Research Program Under the Chinese Steering Committee for Research of Qinghaosu and Its Derivatives - p. 40 21. A. WHO Interest in China’s Artemisinin Antimalarials - p. 41 22. B. The Chinese Steering Committee for Qinghaosu Research and Its Tasks - p. 42 23. C. Joint Projects Between the Chinese Steering Committee for Qinghaosu Research and WHO/TDR - p. 44 24. D. Raising the Standards of New-Drug Research and Production Specifications - p. 48 25. E. Surveys into Artemisia annua Linnaeus Resources and a Base for Artemisinin Production - p. 50 26. F. Preparing for the Global Market - p. 52 27. G. Termination of the Chinese Steering Committee for Qinghaosu Research - p. 52 28. 1.5. Management of Artemisinin Antimalarial Projects - p. 53 29. A. Clear Direction and Goals - p. 54 30. B. Forward-Looking Innovation - p. 55 31. C. New Centralized Management - p. 56 32. D. Mutual Aid and Strength in Numbers - p. 57 33. E. Respecting Knowledge and Talent - p. 58 34. Chapter 2. Agronomics and Biology of Artemisia annua L. - p. 69 35. 2.1. Propagation and Cultivation of Artemisia annua - p. 69 36. A. Botanical and Medicinal Properties - p. 69 37. B. Resource Distribution and Origin - p. 71 38. C. Propagation - p. 73 39. D. Cultivation - p. 84 40. 2.2. Cellular Engineering of Artemisia annua - p. 90 41. A. Overview of Tissue and Organ Culturing - p. 90 42. B. Hairy Root Cultures - p. 92 43. C. Induction of Shoot Clusters - p. 93 44. D. Hairy Roots and Adventitious Shoots Cultured in Bioreactors - p. 94 45. E. Establishment of Genetic Transformation System - p. 95 46. Acknowledgments - p. 98 47. 2.3. Biosynthetic Pathways and Bioengineering of Artemisinin - p. 99 48. A. Biosynthetic Pathways - p. 99 49. B. Genes Involved in Biosynthesis - p. 102 50. C. Regulation of Artemisinin Biosynthesis - p. 106 51. D. Artemisinin and Precursors Synthesis in Plant Bioreactors - p. 111 52. E. Combinatorial Biosynthesis of Artemisinin and Precursors in Microorganisms - p. 112 53. F. Other Studies Related to Artemisinin Biosynthesis - p. 115 54. Chapter 3. Artemisinin Chemical Research - p. 129 55. Chapter 4. Artemisinin Derivatives and Analogues - p. 177 56. Chapter 5. Artemisinin and Derivatives: Pharmacodynamics, Toxicology, Pharmacokinetics, Mechanism of Action, Resistance, and Immune Regulation - p. 197 57. 5.1. Antimalarial Pharmacodynamics - p. 198 58. A. Effects on the Malaria Parasite’s Erythrocytic Stage - p. 198 59. B. Effects of Artemisinin on Malaria Parasite’s Exoerythrocytic Stage - p. 206 60. C. Effect of Artemisinins on Chloroquine-Resistant Strain of Plasmodium berghei In Vivo - p. 208 61. 5.2. Toxicology - p. 211 62. A. Studies in the 1970s - p. 211 63. B. Studies in the 1980s - p. 213 64. C. Trends in Toxicology Research From the 1990s Onward - p. 221 65. D. Conclusions - p. 224 66. Acknowledgments - p. 224 67. 5.3. Pharmacokinetics of Artemisinin and Its Derivatives - p. 225 68. A. Artemisinin - p. 225 69. B. Dihydroartemisinin - p. 246 70. C. Artemether - p. 252 71. D. Artesunate - p. 263 72. Acknowledgments - p. 270 73. 5.4. Antimalarial Mechanisms of Artemisinin and Its Derivatives - p. 270 74. A. Morphological Effects on Malaria Parasites - p. 270 75. B. Effects of Artemisinins on Parasitic Biochemical Metabolism - p. 282 76. C. Further Research Developments in Antimalarial Mechanism of Action of Artemisinin and Its Derivatives (Artemisinins) - p. 300 77. 5.5. Resistance of Plasmodium falciparum to Artemisinins - p. 311 78. B. Latest Developments in Resistance Research: Clinical and Genetic - p. 317 79. 5.6. Immune Regulation Effects of Artemisinin and Its Derivatives - p. 319 80. A. Nonspecific Immunity - p. 319 81. B. Humoral Immunity - p. 323 82. C. Cellular Immunity - p. 325 83. Chapter 6. Artemisinin and Derivatives: Clinical Studies - p. 353 84. 6.1. Artemisinin Clinical Trials - p. 354 85. A. Early Clinical Research on Oral and Injectable Formulations - p. 354 86. B. Artemisinin Suppositories - p. 357 87. 6.2. Artesunate - p. 363 88. A. Intravenous Artesunate - p. 363 89. B. Intramuscular Artesunate in Treating Falciparum Malaria and Comparison With Piperaquine - p. 375 90. C. Artesunate Tablets - p. 379 91. 6.3. Artemether - p. 388 92. A. Phase I Clinical Trial - p. 389 93. B. Phase II Clinical Trials - p. 391 94. C. Phase III Clinical Trial of Artemether-Oil Injections - p. 393 95. 6.4. Dihydroartemisinin Tablets - p. 396 96. A. Phase I Clinical Trial - p. 396 97. B. Phase II Clinical Trials - p. 398 98. C. Phase III Clinical Trials - p. 401 99. D. Conclusion - p. 401 100. 6.5. Evaluation of Parasite Clearance Speeds and Exploration of Regimens - p. 403 101. A. Parasite Clearance Rate and the Concepts of R Fever and T Fever, and R Coma and T Coma - p. 403 102. B. Exploration of Artemisinins’ Treatment Regimens - p. 406 103. 6.6. Artemisinins in Treating Other Parasitic Diseases - p. 407 104. A. Schistosomiasis Prevention - p. 407 105. B. Piroplasmosis - p. 408 106. C. Paragonimiasis - p. 409 107. D. Clonorchiasis - p. 409 108. E. Toxoplasmosis - p. 409 109. Chapter 7. Artemether and Lumefantrine Tablets (Coartem) - p. 415 110. 7.1. Lumefantrine - p. 416 111. 7.2. Compound Artemether Tablets (Artemether–Lumefantrine Combination) - p. 433 112. Chapter 8. Artemisinin–Naphthoquine Phosphate Combination (ARCO) - p. 483 113. 8.1. Naphthoquine Phosphate Research - p. 484 114. B. Pharmacodynamics - p. 486 115. C. General Pharmacology - p. 501 116. D. Non-Clinical Pharmacokinetic Studies in Animals - p. 504 117. E. Non-Clinical Pharmacokinetics: Action Mechanism - p. 509 118. F. Toxicology - p. 514 119. G. Naphthoquine Phosphate Tablets Clinical Trials - p. 522 120. H. Naphthoquine Phosphate Tablets: Key Clinical Findings, Discussion, and Conclusion - p. 535 121. 8.2. Artemisinin–Naphthoquine Phosphate Combination - p. 538 122. A. Preclinical Pharmacology Studies - p. 538 123. B. Clinical Trials - p. 551 124. Chapter 9. Artemisinins and Pyronaridine Phosphate Combination - p. 571 125. Chapter 10. Dihydroartemisinin and Artemisinin in Combination With Piperaquine (Artekin, Artequick); Primaquine and Malaria Transmission; and Malaria Elimination - p. 609 126. Index - p. 671
