The construction of this volume has been guided by two personal convictions. Experience in the field of experimental chemotherapy, both in the pharmaceutical industry and academia, has convinced us that recent quantum technological advances in biochemistry, molecular biology, and immunology will permit and, indeed, necessitate an increasingly greater use of rational drug development in the future than has been the custom up to now. In Part l, therefore, we asked our contributors to provide detailed reviews covering the biology of the malaria parasites and their relation with their hosts, the experimental procedures including culture techniques that are necessary to take a drug from primary screening to clinical trial, and an account of antimalarial drug resistance. Our second conviction is that many research workers are all too loath to learn from the lessons of the past. For this reason we asked the contributors to Part 2 of this volume to review very thoroughly the widely scattered but voluminous literature on those few chemical groups that have provided the antimalarial drugs in clinical use at the present time. Much can be learned from the history of their development and the problems that have arisen with them in man. Some indeed may still have much to offer if they can be deployed in better ways than they are at present. This question has been taken up by several authors.

Inhalt

Antimalarial Drugs in Current Use.- 1 4-Aminoquinolines.- A. Introduction.- I. History.- II. Treatment of Rheumatoid Arthritis.- B. Structure, Antimalarial Activity and Toxicity.- I. Compounds Considered.- II. Structure-Activity Relationships.- III. Oral and Parenteral Toxicity.- C. Methods of Analysis.- I. Induced Fluorescence.- II. Spectrophotofluorometry.- III. Gas-Liquid Chromatography.- IV. Spectrophotometry.- D. Metabolism.- I. General Considerations.- II. Absorption.- III. Tissue Distribution.- IV. Localisation of 4-Aminoquinolines Within Organs.- V. Biotransformation.- E. Pharmacokinetics.- I. Plasma Half-lives.- II. Pharmacokinetic Constants.- F. Modes of Action.- I. Introduction.- II. The Ferriprotoporphyrin IX Drug Complex.- III. Inhibition of Lysosomal Function.- IV. Binding to Major Cellular Constituents.- G. Drug Resistance.- References.- 2 Quinine and Quinine Analogues.- A. Introduction.- I. Scope of the Chapter; Literature Review.- II. Historical Review.- B. Chemistry.- I. Occurrence.- II. Structure.- III. Analytical Methods.- C. Mode of Action.- I. Activity.- II. Structure-Activity Relationships.- III. Molecular Pharmacology.- D. Pharmacokinetics and Metabolism.- I. Pharmacokinetics.- II. Metabolism.- E. Toxicity.- I. Introduction.- II. Animal Tolerance.- III. Human Tolerance.- F. Deployment.- I. Antimalarial Activity in Man.- II. Use of Quinine as an Antimalarial Agent.- G. Drug Resistance.- I. Production of Resistance in Animals.- II. Resistance in Man.- H. Conclusion.- References.- 3 8-Aminoquinolines.- A. Introduction.- B. Chemistry.- I. Introduction.- II. Structure.- III. Assay Methods.- C. Modes of Action.- I. Introduction.- II. Radical Cure and Prevention of Relapses; Deployment.- III. Causal Prophylaxis.- IV. Gametocytocidal and Sporontocidal Effects of Primaquine.- V. Summary of Modes of Action.- D. Pharmacokinetics and Metabolism.- E. Toxicity.- I. Introduction.- II. Neurotoxicity.- III. General Toxicity of the Pamaquine Type.- IV. Primaquine-Induced Haemolytic Anaemia, G6PD Deficiency and Malaria.- V. Isomerism.- F. Drug Resistance.- References.- 4 Sulphonamides and Sulphones.- A. Introduction.- B. Chemistry.- I. Structure.- II. Physicochemical Properties.- III. Assay Methods.- C. Mode of Action.- I. Bacteria.- II. Plasmodia.- III. Stages of Plasmodia Influenced.- D. Human Pharmacokinetics and Metabolism.- I. Sulphonamides.- II. Sulphones.- E. Toxicity.- I. Sulphonamides.- II. Sulphones.- F. Chemotherapy in Experimental Models.- I. Activity Against Non-Human Plasmodia.- II. Activity on Human Plasmodia in Monkeys and in Insect Vectors.- G. Deployment in Man.- I. Sulphonamides.- II. Sulphones.- H. Drug Resistance.- I. Experimental Resistance in Non-Human Plasmodia.- II. Resistance to Sulphonamides and Sulphones in Human Plasmodia.- J. Role of Sulphonamides and Sulphones as Antimalarials.- References.- 5 Dihydrofolate Reductase Inhibitors.- A. Introduction.- B. Proguanil (Chlorguanide).- I. Chemistry and Assay.- II. Metabolism and Pharmacokinetics.- III. Toxicity.- IV. Mode of Action.- V. Deployment.- VI. Resistance.- C. Pyrimethamine.- I. Chemistry and Assay.- II. Metabolism and Pharmacokinetics.- III. Toxicity.- IV. Mode of Action.- V. Deployment.- VI. Resistance.- References.- Novel Methods of Drug Development.- 6 Drug Combinations.- A. Introduction.- B. Complementary Combinations.- I. Drugs Affecting Different Stages of the Life Cycle.- II. Drugs Affecting the Same Stages of the Life Cycle.- C. Additive Combinations.- D. Potentiating Combinations.- I. Compounds Acting on Folate Pathways.- II. Other Compounds.- E. Conclusion.- References.- 7 Repository Preparations.- A. Introduction.- I. The Need.- II. Attributes of a Repository Preparation.- B. Approaches to Repository Antimalarial Drugs.- I. Tissue-Held Drugs.- II. Drugs Incorporated in Polymers and in Physical Devices.- III. Poorly Soluble Salts and Derivatives.- C. Laboratory Test Methods.- I. Biological Response.- II. Rate of Release Studies.- D. Major Types of Drugs Investigated.- I. 4-Aminoquinolines.- II. Quinolinemethanols.- III. Cycloguanil Pamoate.- IV. Pyrimethamine Pamoate.- V. 2,4-Diamino-6-(2-Naphthylsulphonyl)Quinazoline (WR 158122).- E. Closing Comments.- References.- 8 Cell Targeting of Primaquine.- A. Introduction.- B. Chemotherapy Methods.- I. Experimental Malaria Infection.- II. Chemotherapeutic and Toxicity Parameters.- III. Primaquine.- C. Primaquine Entrapped in Liposomes.- I. Preparation of Primaquine Liposomes.- II. Toxicity and Therapeutic Activity.- III. Pharmacokinetics and Tissue Distribution.- IV. Discussion.- D. Primaquine Linked to Asialofetuin.- I. Amino Acid and Peptide Derivatives of Primaquine.- II. Asialofetuin-Primaquine Conjugates.- E. Conclusions.- References.- Recent Developments in Antimalarials.- 9 Drugs with Quinine-like Action.- A. Introduction.- B. Quinolinemethanols.- I. WR 30090.- II. Mefloquine.- III. WR 184806.- IV. WR 226253.- C. Phenanthrenemethanols.- I. WR 33063.- II. WR 122455.- III. Halofantrine.- D. Pyridinemethanols.- I. WR 180409.- II. WR 172435.- E. Conclusions.- References.- 10 8-Aminoquinolines.- A. Introduction.- B. Recent Research.- C. Toxicology.- D. Summary.- E. Conclusions.- References.- 11 Lapinone, Menoctone, Hydroxyquinolinequinones and Similar Structures.- A. Introduction.- B. Chemistry.- I. Structure-Activity Relationships.- II. Assay Methods.- C. Modes of Action.- D. Pharmacokinetics and Metabolism.- E. Toxicity.- F. Deployment.- G. Drug Resistance.- H. Future Prospects.- References.- 12 4-Aminoquinolines and Mannich Bases.- A. Introduction.- B. 4-Aminoquinolines.- I. Exploratory Work.- II. Molecular Biology.- III. Quantitative Structure-Activity Relationships.- IV. Primate Studies.- V. Clinical Studies.- C. Mannich Bases.- I. Exploratory Work.- II. Molecular Biology.- III. Primate Studies.- IV. Toxicology.- D. Conclusions.- References.- 13 Triazines, Quinazolines and Related Dihydrofolate Reductase Inhibitors.- A. General Introduction.- B. Dihydrotriazines.- I. Introduction.- II. Chemistry.- III. Structure-Activity Relationships.- IV. Clinical Properties.- V. Pharmacology.- VI. Other Biological Activities Shown by Dihydrotriazines.- C. Quinazoline and Related Dihydrofolate Reductase Inhibitors.- I. 2,4-Diaminoquinazolines.- II. Ring Aza Analogues.- References.- 14 Antibiotics.- A. Introduction.- B. Chemistry.- I. Tetracyclines.- II. Clindamycin (7-Chlorolincomycin).- C. Modes of Action.- I. Tetracyclines.- II. Clindamycin.- D. Pharmacokinetics and Metabolism.- I. Tetracyclines.- II. Clindamycin.- E. T…