Antimalarial Drugs I: Biological Background, Experimental Methods, and Drug Resistance

ISBN-13: 9783642692536 / Angielski / Miękka / 2011 / 484 str.

A.L. Jr. Ager;V. Boonpucknavig;S.-C. Chou

Opis

Of all the parasitic diseases that beset man in the warmer parts of the world, malaria is still the major cause of morbidity and mortality. In spite of intensive efforts to interrrupt its transmission malaria still threatens over 800 million people, more than one-fifth of the world's population. Malignant tertian malaria caused by Plasmodium Jalciparum probably kills a million every year. Vivax malaria temporarily incapacitates millions more. The search for antimalarial drugs, both natural and syn. thetic, has been and continues to be one of the most challenging and, at times, rewarding exercises ever undertaken by; hemists and biologists. The magnitude of the effort is reflected by the fact that, in the last 15 years, well over 250000 compounds have been screened for antimalarial activity in just one programme, that carried out under the auspices of the Walter Reed Army Institute of Research, not to mention sporadic studies undertaken by other research workers and organisations. While most people engaged in the search for new drugs agree that a rational approach based on knowledge of the intimate biochemical pathways of the target cells would be ideal as well as intellectually satisfying, most are reluctantly obliged to concede that, up to the present time, the chances of success following a more or less empirical search have been far greater. Spectacular advances in molecular biology and biochemistry in recent years, however, are rapidly changing this situation.

Spis treści

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.