Inhibition of Folate Metabolism in Chemotherapy

Trimethoprim/Sulfamethoxazole: An Overview.- A. Introduction.- B. Mechanisms of Action.- C. Resistance.- I. Chromosome-Mediated Resistance.- II. Plasmid-Mediated Resistance.- III. Thymidine Dependence.- D. Clinical Use of TMP/SMX.- I. Approved Indications in the United States.- II. Other Important Uses.- E. Use of TMP or SMX as Single Agents.- F. Adverse Effects.- G. Summary.- References.- Pharmacology and Biochemistry.- 1 Functions of Tetrahydrofolate and the Role of Dihydrofolate Reductase in Cellular Metabolism.- A. General.- B. Occurrence of Folates.- C. Functions of Tetrahydrofolate: Cofactors.- I. Formate and Equivalents.- 1. Purine Biosynthesis.- II. Formaldehyde Equivalents, Hydroxymethyl, and Methyl Derivatives.- 1. Methionine Biosynthesis.- 2. Thymidylate Synthesis.- 3. Vitamins and Other Metabolites.- D. Origins of Cellular Folates.- E. Transport Systems.- I. Selective Rescue.- F. Mechanism of Action of TMP/SMX.- I. Thymineless Death.- G. Summary.- References.- 2 Sulfonamides: Structure-Activity Relationships and Mechanism of Action.- A. Introduction.- B. Development of Sulfonamides and Sulfones.- I. Sulfonamides.- II. Sulfones.- III. Antimicrobial Spectrum.- C. Structure and Biological Activity.- I. Structure-Activity Relationship.- II. Physicochemical Properties and Antimicrobial Activity.- 1. Water Solubility.- 2. Lipid Solubility.- 3. Protein Binding.- III. Pharmacokinetics and Metabolism.- 1. Sulfonamides.- 2. Sulfones.- IV. Half-Life.- D. Mode of Antimicrobial Action.- I. Folic Acid Metabolism.- II. Action of Sulfonamides and Sulfones.- 1. Selectivity of Action.- III. Synergism with Dihydrofolate Reductase Inhibitors.- IV. Drug Resistance.- E. Present Status in Therapeutics.- References.- 3 Dihydrofolate Reductase.- A. Introduction.- B. Assay and Kinetic Studies.- C. Mechanism of Action.- D. Basis of Selectivity.- I. Kinetic Studies.- II. Inhibitor Binding Analysis.- III. Enzyme Conformation and Cooperativity.- IV Amino Acid Sequences.- V. Three-Dimensional Structures of DHFR.- E. Plasmid-Coded Reductases.- F. Genetics of DHFR.- References.- 4 Antibacterial Activity.- A. Introduction.- B. In Vitro Activity.- I. Effects of Medium and Size of Inoculum.- II. Bacteriostatic Activity.- III. Bactericidal Activity.- IV. Demonstration of Synergy.- C. Synergy and Sulfonamide-Resistant Strains.- D. Reversal of Activity of TMP.- E. Development of Resistance.- F. Spectrum of Activity of TMP/SMX.- G. Choice of Sulfonamide.- H. 2,4-Diaminopyrimidines as Single Agents.- J. Susceptibility Testing.- References.- 5 Selective Inhibitors of Bacterial Dihydrofolate Reductase: Structure-Activity Relationships.- A. Introduction.- B. Historical Perspective.- C. Some General Requirements for DHFR Inhibition and Antibacterial Activity.- D. Inhibitors of Specific DHFRs.- I. The 5-Phenyl Derivatives and Related Compounds.- II. 5-Benzyl-2,4-Diaminopyrimidines and Close Relatives.- 1. The 6-Unsubstituted Derivatives.- 2. 6-Substituted Derivatives.- 3. Substitution of a Heterocyclic Ring for the Benzene Moiety.- 4. Variations in the Bridge Between the Pyrimidine and Benzene Rings.- III. The 1,2-Dihydro-1,3,5-Triazines.- IV. Bicyclic Analogs of the Diaminopyrimidines.- E. Discussion.- F. Conclusion.- References.- 6 Kinetics of Antibacterial Effects.- A. Introduction: Bacterial Growth Kinetics in the Presence of Folate Inhibitors.- B. Sulfonamides (Synthetase Inhibitors).- I. Effect of Sulfonamides on Generation Rates of E. coli.- C. Trimethoprim (TMP): Dihydrofolate Reductase Inhibitor.- I. Effect of TMP on Generation Rates of E. coli.- II. Influence of TMP Concentration and Inoculum Size on the “Bactericidal” Effect of TMP.- III. Reversibility of TMP Action.- IV. Influence of Culture Broth Constituents on Biphasic Inhibition.- V. Development of Resistance Against Dihydrofolic Acid Reductase Inhibitors.- D. Combined Action of Sulfonamides and Trimethoprim (Folate Inhibitors).- I. Effect of TMP/SMX on Generation Rates of E. coli.- II. Influence of Inhibitory Power and Concentration of Sulfonamides or Sulfones on the Degree of Synergism.- III. Influence of Inhibitory Power of TMP Derivatives on the Degree of Synergism and Maximal Possible Effect.- IV. Selection Criteria for Combination of TMP and TMP Derivatives with Sulfonamides.- V. Mode of Action of Sulfonamides, TMP, and Their Combinations.- 1. Sulfonamides.- 2. TMP.- 3. Combinations of Sulfonamides and TMP.- References.- 7 Disposition and Metabolism of Trimethoprim, Tetroxoprim, Sulfamethoxazole, and Sulfadiazine.- A. Introduction.- B. Drug Disposition.- I. Drug Absorption.- II. Distribution into Biologic Fluids and Tissues.- 1. Physicochemical Properties that Influence Distributions..- 2. Relationship Between Plasma and Tissue Concentrations.- III. Excretion.- IV. Metabolism.- 1. Trimethoprim.- 2. Tetroxoprim.- 3. Sulfamethoxazole.- 4. Sulfadiazine.- C. Drug Assay Methods.- I. Trimethoprim and Related Benzylpyrimidines.- 1. Spectrofluorometric Methods.- 2. Quantitative Thin Layer Chromatography.- 3. High Pressure Liquid Chromatographic Methods.- 4. Gas-Liquid Chromatographic Analysis.- 5. Microbiologic Procedures.- 6. Other Methods.- II. Sulfonamides.- 1. Spectrophotometric Methods.- 2. Quantitative Thin Layer Chromatography.- 3. High Pressure Liquid Chromatography Methods.- D. Conclusion.- References.- 8 Preclinical Toxicity Testing of Co-trimoxazole and Other Trimethoprim/ Sulfonamide Combinations.- A. Introduction.- B. General Pharmacodynamic Actions.- I. Trimethoprim.- II. Trimethoprim and Sulfamoxole.- C. Acute Toxicity.- I. Trimethoprim, Sulfamethoxazole, and Co-trimoxazole.- II. Trimethoprim and Sulfamethoxypyridazine.- D. Subacute and Chronic Toxicity Tests.- I. Trimethoprim.- 1. Rats.- 2. Monkeys.- 3. Other Species.- II. Trimethoprim and Sulfamethoxazole.- 1. Rats.- 2. Rabbits.- 3. Monkeys.- E. Combinations of Trimethoprim and Other Sulfonamides.- I. Trimethoprim and Sulfafurazole.- II. Trimethoprim and Sulfadiazine.- III. Trimethoprim and Sulfamoxole.- IV. Trimethoprim and Sulfamethoxypyrazine.- F. Special Studies of the Thyroid and Trimethoprim/Sulfonamide Combinations.- G. Other Actions of Trimethoprim Alone or Combined with Sulfonamides.- I. Co-trimoxazole and Immunosuppression.- II. Local Effects of Intramuscular Injection of Trimethoprim and Various Sulfonamides.- III. Co-trimoxazole and Renal Failure.- H. Reproductive Toxicology.- I. Fetal Toxicity Tests.- 1. Rats.- 2. Rabbits.- II. Fertility Tests.- 1. Rats.- 2. Rabbits.- 3. Hamsters.- 4. Conclusions.- 5. Other Related Information.- III. Reproductive Toxicity of Trimethoprim Combined with Other Sulfonamides.- 1. Trimethoprim and Sulfamoxole.- 2. Trimethoprim and Sulfamethoxypyrazine J. Mutagenicity.- J. Mutagenicity.- I. Point Mutation Tests in Bacteria.- II. Human Cytogenetic Studies References.- References.- Clinical Pharmacology.- 9 Adverse Effect of Co-trimoxazole.- A. Introduction.- B. Gastrointestinal Disorders.- I. Upper Gastrointestinal Symptoms.- II. Lower Gastrointestinal Symptoms.- C. Skin Disorders.- I. Toxic Erythema.- II. Other Skin Reactions.- III. Sulfamethoxazole or Trimethoprim?.- D. Renal Disorders.- E. Haematological Disorders.- I. Folic Acid Deficiency.- II. Leucopenia/Agranulocytosis.- III. Thrombocytopenia.- IV. Haemolytic Anaemia.- F. Jaundice.- I. Liver Damage.- II. Hyperbilirubinaemia of the Newborn.- G. Pregnancy.- H. Miscellaneous.- J. Drug Interactions.- I. Pyrimethamine.- II. Azathioprine.- III. Warfarin.- IV. Phenytoin.- V. Hypoglycaemic Agents.- K. Conclusions.- References.- 10 Clinical Pharmacokinetics of Co-trimoxazole.- A. Introduction.- B. Absorption and Biologic Half-Lives.- C. Distribution.- I. Plasma.- II. Cerebrospinal Fluid.- III. Aqueous Humor.- IV. Breast Milk.- V. Prostatic and Seminal Material.- VI. Vaginal Fluid.- VII. Placental and Fetal Material.- VIII. Bile Fluid.- IX. Erythrocytes.- X. Bone.- XI. Other Tissues and Organs.- D. Metabolism.- E. Elimination.- F. Interactions.- References.- 11 Resistance: Genetics and Medical Implications.- A. Introduction.- B. Resistance to Sulfonamides.- I. Definition.- II. Natural Resistance.- III. Acquired Resistance.- C. Resistance to Trimethoprim.- I. Definition.- II. Natural Resistance.- III. Acquired Resistance.- D. Mechanisms of Acquired Resistance to Sulfonamides.- I. Results of Mutations.- 1. Decreased Permeability.- 2. Hyperproduction of p-Aminobenzoic Acid.- 3. Altered Dihydropteroate Synthase.- II. Acquisition of R Factors.- E. Mechanism of Acquired Resistance to Trimethoprim.- I. By Mutation.- 1. Thymineless Organisms.- 2. Modification of Dihydrofolate Reductase.- II. Plasmid-Mediated Resistance.- 1. Transferable.- 2. Nontransferable.- F. Medical Implications.- I. Sulfonamide-Resistant Strains.- II. Sulfonamide-Sensitive, Trimethoprim-Resistant Strains.- III. Emergence of Resistant Strains During Therapy.- G. Epidemiologic Overview of Resistance to Trimethoprim.- I. Gram-Positive Bacteria.- II. Gram-Negative Bacteria.- References.- Clinical Studies.- 12 Trimethoprim Alone: Clinical Uses.- A. Introduction.- B. Microbiologic and Pharmacokinetic Properties.- C. Relation of Sensitivities and Pharmacokinetics to Therapy of Urinary Tract Infections.- I. General.- II. Uncomplicated Urinary Tract Infections.- III. Complicated Urinary Tract Infections.- D. Prophylaxis.- I. Recurring Urinary Infection in Women and Children.- II. Immunosuppressed Patients.- E. Adverse Reactions and Safety.- I. General.- II. Dermatologic.- III. Gastrointestinal.- IV. Hematologic.- F. Bacterial Resistance.- I. General.- II. Finnish Experience.- III. Effect on Fecal Flora.- G. Conclusion.- References.- 13 Inhibitors of Dihydrofolate Reductase as Antiprotozoal Agents.- A. Introduction.- B. Points of Possible Therapeutic Attack.- C. Antimalarial Therapeutics.- I. Early Trials.- II. Clinical Cure with Pyrimethamine.- III. Causal Prophylaxis.- IV. Suppression and Mass Prophylaxis.- V. Gametocyticidal Effects.- VI. Radical Cure.- VII. Drug Resistance.- VIII. Combination with Sulfonamides and Sulfones.- 1. Suppressive and Clinical Cure.- 2. Effect on Other Sporozoa.- References.- 14 Pediatric Uses of Sulfonamides, Trimethoprim, and the Combination.- A. Introduction.- B. Hemophilus influenzae Infections.- I. Otitis Media.- 1. Acute.- 2. Serous and Chronic.- II. Sinusitis.- III. Prophylaxis to Prevent Secondary Infection.- C. Meningitis.- D. Urinary Tract Infections.- I. Acute.- II. Structural Defects of the Urinary System.- III. Prevention.- IV. Therapy of Periurethral and Rectal Flora.- V. Chlamydial Infections.- E. Pneumocystis carinii Pneumonia.- I. Therapy.- II. Prevention.- F. Enteric Diseases.- I. Salmonellosis.- II. Shigellosis.- III. Yersinia Infections.- 1. Acute Enteritis.- 2. Chronic Enteritis.- 3. Mesenteric Adenitis.- G. Miscellaneous Conditions.- I. Chronic Granulomatous Disease.- II. Osteomyelitis.- III. Ascending Cholangitis.- References.- 15 Use of Co-trimoxazole in Urinary Tract Infection.- A. Introduction.- B. Co-trimoxazole in Acute Urinary Tract Infection.- I. Epidemiology of Resistance.- 1. Types of Resistance.- II. Effects of Carriage Sites.- 1. Effect on Gut Flora.- 2. Effect on Urethral Colonisation.- III. Overtreatment.- C. Control of Recurrent Infection.- D. Role of the Combination.- I. Contrasting Effects of Trimethoprim and Sulfonamide in the Urine.- II. Toxicity.- References.- 16 Treatment of Genital Infections with Trimethoprim, Sulfonamides, and Combinations.- A. Introduction.- B. Treatment of Gonorrhea with Trimethoprim/Sulfamethoxazole.- I. Uncomplicated Anogenital Infection.- II. Rectal Infection.- III. Pharyngeal Infection.- IV. In Vitro Studies and Treatment of Gonorrhea with Trimethoprim/Sulfamethoxazole.- C. Infections Due to Chlamydia trachomatis.- I. Postgonococcal Urethritis.- II. Nongonococcal Urethritis.- III. Lymphogranuloma Venereum.- D. Chancroid.- E. Syphilis.- References.- 17 Treatment of Enteric Infections and Combinations.- A. Escherichia coli Diarrhea.- I. Introduction.- II. Trimethoprim/Sulfamethoxazole Treatment of E. coli Diarrhea.- 1. In Vitro Studies.- 2. Clinical Studies.- III. Summary.- B. Isospora belli Infections.- I. Introduction.- II. Trimethoprim/Sulfamethoxazole Treatment of an Isospora belli Infection.- C. Salmonella Infections.- I. Introduction.- 1. Typhoidal and Paratyphoidal Salmonella Infections.- 2. Non-Typhoidal Salmonella Infections.- II. Trimethoprim/Sulfamethoxazole in the Treatment of Salmonella typhi Infections.- 1. Therapeutic Studies in Antibiotic-Sensitive S. typhi Infections.- 2. Studies in Infections Due to Chloramphenicol-Resistant S. typhi Strains.- 3. Trimethoprim/Sulfamethoxazole Treatment of Typhoid Carriers.- 4. Adverse Effects.- 5. Summary.- III. Trimethoprim Alone in Treatment of Enteric Fever.- IV. Trimethoprim/Sulfamethoxazole Therapy in Non-Typhoidal Salmonellosis.- 1. In Vitro Studies.- 2. Clinical Studies.- 3. Summary.- D. Shigella.- I. Introduction.- II. Trimethoprim/Sulfamethoxazole Treatment in Shigellosis.- 1. In Vitro Studies.- 2. Clinical Studies.- 3. Summary.- E. Vibrio cholerae Infections.- I. Introduction.- II. Trimethoprim/Sulfamethoxazole Treatment in Cholera.- 1. In Vitro Studies.- 2. Clinical Studies.- 3. Summary.- F. Yersinia enterocolitica Infections.- I. Introduction.- II. Trimethoprim/Sulfamethoxazole and Yersinia enterocolitica.- 1. In Vitro Studies.- 2. Clinical Report.- 3. Summary.- References.- 18 Prostatitis.- A. Introduction.- B. Classification and Description of Patient Categories.- C. Acute and Chronic Bacterial Prostatitis.- I. Diagnosis.- II. Pathology.- III. Prostatic Immunoglobulins.- IV. The Antibacterial Factor in Prostatic Fluid.- V. Treatment.- D. Nonbacterial Prostatitis.- References.- 19 Co-trimoxazole in Chest Infections Including its Long-Term Use in Chest Disease.- A. Introduction.- B. Exacerbations of Chronic Bronchitis.- I. Levels of Two Components in Sputum.- II. Comparative Trials.- C. Other Acute Conditions.- I. Pneumocystis carinii Pneumonia.- D. Long-Term Treatment.- E. Parenteral TMP/SMX.- F. Alternative Drugs.- G. Trimethoprim Alone.- H. Future Developments.- References.- 20 Treatment of Miscellaneous and Unusual Infections with Trimethoprim and Trimethoprim/Sulfonamide Combinations.- A. Introduction.- B. Brucellosis.- C. Toxoplasmosis.- D. Nocardiosis.- E. Atypical Mycobacteria.- F. Mycoses.- I. Histoplasmosis.- II. Paracoccidioidomycosis.- III. Phycomycosis.- IV. Chromomycosis.- G. Pseudomonas Infections.- I. Pseudomonas pseudomallei.- II. Pseudomonas cepacia and Pseudomonas maltophilia.- H. Other Infections.- I. Bubonic Plague.- II. Rickettsiosis.- 1. Boutonneuse Fever.- 2. Q Fever.- III. Legionella pneumophila and Pittsburgh Pneumonia Agent Infections.- IV. Isospora belli Infections.- V. Malakoplakia.- VI. Pediculosis.- References.