Antimalarial Drugs I

The Malaria Parasites.- 1 Life Cycles.- A. Introduction.- B. General Characters of Plasmodium s.l..- C. Life Cycle of Plasmodium Species.- I. Life Cycle in Mammalian Malaria.- II. Life Cycle in Avian Malaria.- III. Life Cycle in Reptilian Malaria.- D. Specific Examples.- I. Human Species of Plasmodium.- II. Rodent Malaria Parasites.- III. Hepatocystis kochi (Syn. Plasmodium kochi).- E. Abnormal Modes of Transmission.- I. Infection from a Blood Source.- II. Transmission from an Animal Reservoir.- III. Life Cycle in Abnormal Hosts.- References.- 2 Metabolism.- A. Introduction.- B. Biochemical Determinants of Parasite Specificity for the Host Cell.- C. Membrane Proteins of the Infected Erythrocyte.- D. Plasmodial Membrane Proteins.- E. Lipids of Malaria-Infected Erythrocytes.- F. Plasmodial Membrane Lipids.- G. Metabolic Pathways.- I. Carbohydrate Transport and Metabolism.- II. Protein Synthesis.- III. Nucleic Acids.- IV. Lipid Biosynthesis.- V. Vitamins and Cofactors.- H. Biochemical Characteristics of the Erythrocyte and Host-Parasite Relationships.- I. Sickle Cell Haemoglobin.- II. Other Haemoglobins and Thalassaemia.- III. Glucose-6-phosphate Dehydrogenase Deficiency and Reduced Glutathione Content.- IV. Adenosine Triphosphate Deficiency.- J. Cation Alterations.- K. Conclusion.- References.- 3 In Vitro Culture Techniques.- A. Introduction.- B. Asexual Intraerythrocytic Stages.- I. Basic Problems of In Vitro Culture.- II. Techniques of Cultivation.- III. Drug Testing.- IV. New Developments.- V. Conclusion.- C. Tissue Stages.- I. Introduction.- II. Avian Studies.- III. Rodent Models.- D. Gametocytogenesis In Vitro.- E. Sporogonic Stages.- F. Conclusions.- References.- Host Responses to Malaria.- 4 Immunity.- A. Introduction.- B. The Clinical Expression of Immunity to Malaria in Man.- C. Malaria Antigens, the Induction of Immunity and Protective Mechanisms in Infection and Vaccination.- I. Specificity of Antimalarial Immune Responses.- II. Immune Response to Sporozoites.- III. Immune Response to the Exoerythrocytic Phase.- IV. Immune Response to the Sexual Stages.- V. Immune Response to Asexual Erythrocytic Parasites.- VI. Evasion of the Immune Response.- VII. The Anatomical and Cellular Bases of Immunity to Malaria.- D. Immunostimulants and Immunological Adjuvants in the Induction of Immune Responses to Malaria.- I. Differentiation Between Non-Specific Immunostimulant and Adjuvant Effects.- II. Mycobacteria and Synthetic Analogues of Their Cell Wall Components as Malaria Vaccine Adjuvants.- III. Non-Bacterial Adjuvants in Malaria Vaccines.- References.- 5 Clinical Pathology.- A. Introduction.- B. Pathogenesis.- I. The Parasites.- II. Host-Parasite Interaction.- C. Clinicopathological Correlation.- I. Uncomplicated Malaria.- II. Complicated Malaria.- References.- Experimental Models.- 6 In Vitro Techniques for Antimalarial Development and Evaluation.- A. Introduction.- B. The Role of In Vitro Methods in Antimicrobial Drug Research.- I. Advantages.- II. Limitations.- III. Specific Applications to Malaria.- C. Short-Term In Vitro Cultures.- I. Plasmodium knowlesi.- II. Plasmodium berghei.- III. Plasmodium falciparum.- D. Continuous Culture Technology for Plasmodium falciparum.- I. Improved Evaluation and Monitoring of Drug Responses.- II. Studies on Mode of Action and Kinetics.- III. A Semiautomated Technique of Antimalarial Evaluation.- IV. Other Applications.- E. The Future Role of In Vitro Techniques.- References.- 7 Use of Avian Malarias (In Vivo).- A. Introduction.- B. Experimental Hosts and Methods.- I. Transmission by Blood Inoculation.- II. Drug Testing.- C. Chemotherapy.- I. Quinine.- II. 4-Aminoquinolines.- III. 8-Aminoquinolines.- IV. Sulphonamides and Sulphones.- V. Antifolates.- VI. Amidinoureas.- VII. Quinolinemethanols.- D. Conclusion.- References.- Chapte 8 Rodent Malaria Models.- A. Introduction.- B. Blood Schizontocides.- I. Single-Dose Regimens.- II. Multiple-Dose Regimens.- C. Tissue Schizontocides.- I. Most's Test.- II. Berberian's Test.- III. Vincke's Test.- IV. Gregory and Peters' Test.- V. Hill's Test.- VI. Fink's Test.- VII. King's Test.- VIII. Rane and Kinnamon's Test.- D. Residual Blood Schizontocides.- I. Schneider's Test.- II. Thompson's Test.- III. Sustained Release Implant Test.- E. Residual Tissue Schizontocides.- References.- 9 Malaria Models in Simian Hosts.- A. Introduction.- B. Use in Blood Schizontocide Studies.- I. Simian Plasmodia.- II. Human Plasmodia.- C. Use in Tissue Schizontocide Studies.- I. Simian Plasmodia.- II. Human Plasmodia.- D. Conclusion.- References.- 10 Surrogate Models for Antimalarials.- A. Isolated Enzyme Systems. M. R. Levy and S.-C. Chou.- I. Introduction.- II. Effects of Chloroquine on Receptor-Mediated Endocytosis.- III. Effects of Chloroquine on Uptake and Transport of Lysosomal Enzymes.- IV. Protease Inhibitors: Effects on Parasite Protease and on Parasite Biosynthetic Processes and Growth.- V. Summary.- B. Protozoa Other than Plasmodium. K. A. Conklin and S.-C. Chou.- I. Introduction.- II. Experimental Models.- III. Conclusion.- C. Drug-Induced Clumping Test. D. C. Warhurst.- I. Introduction.- II. Experimental Approach.- III. Analysis of Autophagic Vacuole Formation.- IV. Insights into Antimalarial Mode of Action.- V. Drug-Screening Applications.- VI. Conclusions.- References.- 11 Interactions Between Chemotherapy and Immunity.- A. Introduction.- B. Immune Responses in Malaria.- I. Innate Resistance.- II. Acquired Immunity.- C. Immunodepression by Malaria Infections.- D. Immune Dependence of Antimalarial Chemotherapy.- E. Immunodepressive Effects of Antimalarial Drugs.- F. Chemotherapy and Induction of Immunity.- G. Immunopathological Changes in Malaria.- I. Tropical Splenomegaly Syndrome.- II. Renal Lesions.- III. Cerebral Malaria.- H. Immunopotentiation and Chemotherapy.- J. Conclusions.- References.- Preclinical and Clinical Trial Techniques.- 12 Preclinical Testing.- A. Introduction.- B. Efficacy Investigations.- I. Empirical Versus Rational Drug Synthesis.- II. Drug-Screening Models.- C. Blood Schizontocidal Testing.- I. Primary Testing.- II. Secondary Testing.- D. Tissue Schizontocidal Testing.- E. Miscellaneous Models.- F. Toxicological Investigations.- I. General.- II. Acute Toxicity.- III. Subacute Toxicity.- IV. Chronic Toxicity.- G. Pharmacodynamic Investigations.- H. Concluding Remarks.- References.- 13 Clinical Trials - Phases I and.- A. Introduction.- I. Objectives of Trials in Individual Subjects.- II. Prerequisites for Administering a New Drug in Man.- III. Definition of Phases for Clinical Trials.- IV. Classification of Antimalarials.- V. Resistance to Schizontocidal Drugs.- VI. Ethical Considerations.- B. Phase I.- I. Initial Trials in Volunteers.- II. Tolerance and Pharmacokinetics in the Target Population.- C. Phase II.- I. General Considerations.- II. Trials in Experimentally Infected Patients or Volunteers.- III. Trials in Naturally Infected Subjects.- References.- 14 Clinical Trials - Phases III and IV and Field Trials.- A. Phase III.- I. Objective and Design of the Studies.- II. Selection of Patients and Risk Factors.- III. Special Tests Required.- B. Phase IV.- I. Safety Studies.- II. Pharmacokinetics.- III. Efficacy Studies.- IV. Symptomatic Treatment of Malaria.- V. Conclusion.- C. Field Trials.- I. Introduction and Objectives.- II. Design and Selection of Participants.- III. Extended Field Trials.- IV. Conclusion.- References.- 15 Pharmacogenetic Factors in Antimalarial Drug Testing.- A. Red-Cell Genetic Factors.- I. The Haemoglobinopathies.- II. Thalassaemias.- III. Enzyme Deficiencies.- B. Acetylator Phenotype.- C. Blood Groups.- D. Conclusion.- References.- Antimalarial Drug Resistance.- 16 History and Current Status of Drug Resistance.- A. Introduction.- B. History of Experimental Research on Antimalarial Drug Resistance.- I. Dihydrofolate Reductase Inhibitors.- II. Naphthoquinones and Related Compounds.- III. Primaquine.- IV. Aminoalcohols Related to Quinine.- C. History of Drug Resistance in Man.- I. Quinine and 4-Aminoalcohols.- II. Mepacrine and 4-Aminoquinolines.- III. Dihydrofolate Reductase Inhibitors.- IV. Primaquine and Other 8-Aminoquinolines.- D. Future Problems and Prospects.- I. Biological Factors in the Dissemination of Chloroquine Resistance.- II. The Geographical Extension of Chloroquine Resistance in P. falciparum.- E. Conclusion.- References.- 17 Evaluation of Drug Resistance in Man.- A. Introduction.- B. Evaluation of Drug Resistance In Vivo.- I. Resistance to Chloroquine.- II. Resistance to Other Antimalarials.- III. Disadvantages of In Vivo Evaluation of Drug Resistance.- C. Evaluation of Drug Resistance In Vitro.- I. Macrotechnique Using Venous Blood Specimens.- II. Microtechnique Using Capillary Blood Specimens.- D. Monitoring of Drug Resistance.- References.- 18 Experimental Production of Drug Resistance.- A. Introduction.- B. Modes of Drug Resistance Development.- C. Techniques.- I. In Vitro Procedure.- II. Semi In Vitro Techniques.- III. Tissue Culture.- IV. In Vivo Techniques.- V. Indirect Methods.- D. Conclusion.- References.