Pharmacology of Fluorides

1: Methods of Analysis for Fluorine.- I. Introduction.- II. Methods of Sample Preparation.- A. Organic Compounds.- 1. The Oxygen-Flask Method.- Procedure for Oxygen-Flask Combustion.- 2. Fusion with Alkali Metals.- Procedure for Alkali Metal Fusion.- 3. Reduction with Alkali Metal in Organic Solvents.- 4. Wickbold Oxyhydrogen Flame Method.- B. Inorganic Samples.- C. Agricultural and Food Samples.- D. Miscellaneous Samples.- III. Methods of Separation.- A. Separation of Fluorosilicic Acid by Distillation.- B. Separation by Pyrohydrolysis.- C. Separation by Diffusion.- D. Separation by Ion-exchange.- E. Chromatographic Separation on Paper and Thin Layers.- F. Other Methods of Separation.- IV. The Detection of Fluoride.- Procedure for the 8-Hydroxyquinoline Test.- V. The Determination of Fluoride.- A. Gravimetric Methods.- 1. Precipitation as Lead Chlorofluoride.- a) Recommended Lead Chlorofluoride Procedure.- ?) Reagents.- ?) Procedure.- 2. Precipitation as Calcium Fluoride.- B. Titrimetric Methods.- 1. Titration with Thorium Solution.- a) Interferences.- b) Direct Titration Procedure.- c) Back-Titration Procedure.- 2. Titration with Aluminum Solution.- 3. Acid-Base Titration of Hydrofluoric Acid.- 4. Titration with Rare Earth Solutions.- 5. Other Titrimetric Methods.- a) Titration with Calcium Solutions.- b) Titrations based on Lead Halofluoride Formation.- c) Titration with Iron(III) Solutions.- d) Titrations based on Fluorosilicic Acid.- C. Colorimetric Methods.- 1. The Alizarin Fluorine Blue Methods.- a) Recommended Lanthanum-Alizarin Fluorine Blue Procedure.- ?) Reagents.- ?) Calibration Graph.- 2. The Bleaching of Zirconium-Dye Complexes.- a) Recommended Zirconium-Eriochrome Cyanine R Procedure.- ?) Reagents.- ?) Calibration Graph.- 3. The Bleaching of Thorium-Dye Complexes.- 4. The Bleaching of Aluminum-Dye Complexes.- 5. Other Colorimetric Methods.- a) Titanium(IV) Complexes.- b) Iron(III) Complexes.- c) Chloranilie Acid Methods.- d) Molybdenum Blue Methods.- D. Polarographic Methods.- E. Direct Electrometric Methods.- F. Radiometric Methods.- G. Catalytic Methods.- H. Determination of Elemental Fluorine.- VI. The Determination of Common Elements in Organic Fluorine Compounds.- A. Carbon, Hydrogen and Nitrogen.- B. Other Halogens, Sulfur and Phosphorus.- References.- 2: Effect of Inorganic Fluoride on Enzymes.- I. General Introduction.- II. Enzymes, Inhibited by Fluoride, Requiring Metal Ions, and Whose Inhibition is Enhanced by Phosphate.- A. Enolase.- B. Phosphoglucomutase.- C. Lecithinase (from Clostridium welchii).- D. Succinic Dehydrogenase.- III. Enzymes, Inhibited by Fluoride, Requiring Divalent Metal Ions.- A. Phosphatases.- 1. Acid Phosphatases.- 2. Alkaline Phosphatases.- B. Pyrophosphatases.- 1. Acid Pyrophosphatases.- 2. Alkaline Pyrophosphatases.- C. Kinases.- D. General.- 1. Cholinesterase.- 2. Glutamine Synthetase.- 3. Alcohol Dehydrogenase (Liver).- 4. ?-Amylase (Ca++-activated).- 5. Comments on Non-Inhibition by Fluoride of some Enzymes Activated by Divalent Metals.- IV. Enzymes Inhibited by Fluoride; No Requirement for Metal Ions Demonstrated.- A. Liver Esterase.- B. 5'1: Methods of Analysis for Fluorine.- I. Introduction.- II. Methods of Sample Preparation.- A. Organic Compounds.- 1. The Oxygen-Flask Method.- Procedure for Oxygen-Flask Combustion.- 2. Fusion with Alkali Metals.- Procedure for Alkali Metal Fusion.- 3. Reduction with Alkali Metal in Organic Solvents.- 4. Wickbold Oxyhydrogen Flame Method.- B. Inorganic Samples.- C. Agricultural and Food Samples.- D. Miscellaneous Samples.- III. Methods of Separation.- A. Separation of Fluorosilicic Acid by Distillation.- B. Separation by Pyrohydrolysis.- C. Separation by Diffusion.- D. Separation by Ion-exchange.- E. Chromatographic Separation on Paper and Thin Layers.- F. Other Methods of Separation.- IV. The Detection of Fluoride.- Procedure for the 8-Hydroxyquinoline Test.- V. The Determination of Fluoride.- A. Gravimetric Methods.- 1. Precipitation as Lead Chlorofluoride.- a) Recommended Lead Chlorofluoride Procedure.- ?) Reagents.- ?) Procedure.- 2. Precipitation as Calcium Fluoride.- B. Titrimetric Methods.- 1. Titration with Thorium Solution.- a) Interferences.- b) Direct Titration Procedure.- c) Back-Titration Procedure.- 2. Titration with Aluminum Solution.- 3. Acid-Base Titration of Hydrofluoric Acid.- 4. Titration with Rare Earth Solutions.- 5. Other Titrimetric Methods.- a) Titration with Calcium Solutions.- b) Titrations based on Lead Halofluoride Formation.- c) Titration with Iron(III) Solutions.- d) Titrations based on Fluorosilicic Acid.- C. Colorimetric Methods.- 1. The Alizarin Fluorine Blue Methods.- a) Recommended Lanthanum-Alizarin Fluorine Blue Procedure.- ?) Reagents.- ?) Calibration Graph.- 2. The Bleaching of Zirconium-Dye Complexes.- a) Recommended Zirconium-Eriochrome Cyanine R Procedure.- ?) Reagents.- ?) Calibration Graph.- 3. The Bleaching of Thorium-Dye Complexes.- 4. The Bleaching of Aluminum-Dye Complexes.- 5. Other Colorimetric Methods.- a) Titanium(IV) Complexes.- b) Iron(III) Complexes.- c) Chloranilie Acid Methods.- d) Molybdenum Blue Methods.- D. Polarographic Methods.- E. Direct Electrometric Methods.- F. Radiometric Methods.- G. Catalytic Methods.- H. Determination of Elemental Fluorine.- VI. The Determination of Common Elements in Organic Fluorine Compounds.- A. Carbon, Hydrogen and Nitrogen.- B. Other Halogens, Sulfur and Phosphorus.- References.- 2: Effect of Inorganic Fluoride on Enzymes.- I. General Introduction.- II. Enzymes, Inhibited by Fluoride, Requiring Metal Ions, and Whose Inhibition is Enhanced by Phosphate.- A. Enolase.- B. Phosphoglucomutase.- C. Lecithinase (from Clostridium welchii).- D. Succinic Dehydrogenase.- III. Enzymes, Inhibited by Fluoride, Requiring Divalent Metal Ions.- A. Phosphatases.- 1. Acid Phosphatases.- 2. Alkaline Phosphatases.- B. Pyrophosphatases.- 1. Acid Pyrophosphatases.- 2. Alkaline Pyrophosphatases.- C. Kinases.- D. General.- 1. Cholinesterase.- 2. Glutamine Synthetase.- 3. Alcohol Dehydrogenase (Liver).- 4. ?-Amylase (Ca++-activated).- 5. Comments on Non-Inhibition by Fluoride of some Enzymes Activated by Divalent Metals.- IV. Enzymes Inhibited by Fluoride; No Requirement for Metal Ions Demonstrated.- A. Liver Esterase.- B. 5'-Adenylic Acid Deaminase.- C. Phosphoglycerate Mutase.- D. Hydrazidase.- V. Enzymes, Inhibited by Fluoride, Containing Trivalent Metal Ions.- A. Catalase.- B. Peroxidase.- VI. Concluding Comments.- References.- 3: Changes in Cell Function Due to Inorganic Fluoride.- I. Introduction.- II. Effect of Fluoride on Metabolic Pathways.- A. Outline of Intermediary Metabolism.- B. Glycolysis.- C. Pyruvate Metabolism and Oxidation in the Tricarboxylic Acid Cycle.- D. Oxidative Phosphorylation.- E. Respiration.- F. Protein Synthesis.- G. The Response of Tissues to Hormones.- H. Fat Metabolism in Adipose Tissue.- I. Lipases.- III. Effects of Fluoride on Physical Activity of Cells.- A. Movement.- 1. Motility.- 2. Phagocytosis.- 3. Contractility.- B. Transport Across Cell Membranes.- 1. Intestinal Epithelium.- 2. Non-Polar Cells.- IV. Effects of Fluoride on the Growth and Development of Cells in Tissue Culture.- V. Concluding Remarks.- References.- 4: Pharmacology of Sodium Fluoride.- I. Introduction.- II. Effect of Sodium Fluoride on Blood Pressure and the Heart.- A. Hypotensive Activity of Fluoride.- B. Pressor Effect of Fluoride.- C. Stimulatory Effect of Sodium Fluoride on Isolated Heart Preparations.- III. Effect of Sodium Fluoride on the Gut.- A. Effect of Fluoride on the Gut, in Vivo.- B. Effect of Fluoride on Dog Gut, in Vitro.- IV. Effect of Sodium Fluoride on Respiration.- V. Summary and Conclusions.- References.- 5: Fluoroamino Acids and Microorganisms.- I. Introduction.- II. Fluoroamino Acids and Cellular Microorganisms.- A. General Toxicity and Effects on Growing Cells.- B. Incorporation of Fluoroamino Acids into Proteins.- C. Effects of Fluoroamino Acids on Specific Cell Functions.- 1. Cell Division.- 2. Motility.- 3. Capsule Formation.- 4. Regulation of Enzyme Synthesis and Activity.- 5. Transport Systems.- 6. Bacterial Sporogenesis.- 7. Respiration and Photosynthesis.- 8. Ribosome Synthesis.- 9. Antibiotic Production.- 10. Maintenance of Diploid State in Fungi.- 11. Virus and Bacteriocin Production.- D. Catabolism of Fluoroamino Acids by Bacteria.- E. Bacterial Adaptation to Fluoroamino Acids.- 1. Physiologic Adaptation.- 2. Amino Acid-Secreting Mutants.- 3. Mutants with Altered Transport Systems.- 4. Mutants with Altered Amino Acyl-tRNA Synthetases.- 5. Mutants with Altered Ribosomes.- References.- 6: Fluorine-Containing Steroids.- I. Introduction.- II. Fluoro Steroids with Respect to Glucogenic, Anti-Inflammatory and Mineralocorticoid Effect.- A. The 9?-Fluoro-Substitution in.- 1. Cortisol.- 2. ?1-Cortisol (Prednisolone).- 3. ?6-Cortisol.- 4. Other Pregnane Derivatives.- B. Fluorination at other Positions and in Combination with 9?-Fluoro.- 1. In Cortisone, Cortisol, Prednisone or Prednisolone.- a) 2?-Fluoro.- b) 4-Fluoro.- c) 6? -Fluoro and 6?,9? -Difluoro.- d) 15?-Fluoro and 9?,15?-Difluoro.- e) 16? -Fluoro, 9?,16?-Difluoro, 6?,16? -Difluoro and 6?,9?,16? -Trifluoro.- f) 16?-fluoro and 9?,16?-Difluoro.- 2. In other Pregnane Derivatives.- a) 1l?-Fluoro.- b) 12? -Fluoro.- c) 17? -Fluoro.- d) 21-Fluoro.- e) Fluorine in 16?,17? -Ketal.- C. Other Groups in.- 1. 9? -Fluorocortisol and 9?-Fluoroprednisolone.- a) 1-Hydroxy.- b) 2? -Methyl.- c) 4-Methyl and 4-Ethyl.- d) 6? - and 6?-Chloro.- e) 6? -Fluoromethyl.- f) 6? -Methoxy.- g) 6? -Methyl.- h) 7? -Acetylthio.- i) 16?-Acetoxy.- j) 16?-Chloro.- k) 16? -Ethyl.- 1) 16? -1: Methods of Analysis for Fluorine.- I. Introduction.- II. Methods of Sample Preparation.- A. Organic Compounds.- 1. The Oxygen-Flask Method.- Procedure for Oxygen-Flask Combustion.- 2. Fusion with Alkali Metals.- Procedure for Alkali Metal Fusion.- 3. Reduction with Alkali Metal in Organic Solvents.- 4. Wickbold Oxyhydrogen Flame Method.- B. Inorganic Samples.- C. Agricultural and Food Samples.- D. Miscellaneous Samples.- III. Methods of Separation.- A. Separation of Fluorosilicic Acid by Distillation.- B. Separation by Pyrohydrolysis.- C. Separation by Diffusion.- D. Separation by Ion-exchange.- E. Chromatographic Separation on Paper and Thin Layers.- F. Other Methods of Separation.- IV. The Detection of Fluoride.- Procedure for the 8-Hydroxyquinoline Test.- V. The Determination of Fluoride.- A. Gravimetric Methods.- 1. Precipitation as Lead Chlorofluoride.- a) Recommended Lead Chlorofluoride Procedure.- ?) Reagents.- ?) Procedure.- 2. Precipitation as Calcium Fluoride.- B. Titrimetric Methods.- 1. Titration with Thorium Solution.- a) Interferences.- b) Direct Titration Procedure.- c) Back-Titration Procedure.- 2. Titration with Aluminum Solution.- 3. Acid-Base Titration of Hydrofluoric Acid.- 4. Titration with Rare Earth Solutions.- 5. Other Titrimetric Methods.- a) Titration with Calcium Solutions.- b) Titrations based on Lead Halofluoride Formation.- c) Titration with Iron(III) Solutions.- d) Titrations based on Fluorosilicic Acid.- C. Colorimetric Methods.- 1. The Alizarin Fluorine Blue Methods.- a) Recommended Lanthanum-Alizarin Fluorine Blue Procedure.- ?) Reagents.- ?) Calibration Graph.- 2. The Bleaching of Zirconium-Dye Complexes.- a) Recommended Zirconium-Eriochrome Cyanine R Procedure.- ?) Reagents.- ?) Calibration Graph.- 3. The Bleaching of Thorium-Dye Complexes.- 4. The Bleaching of Aluminum-Dye Complexes.- 5. Other Colorimetric Methods.- a) Titanium(IV) Complexes.- b) Iron(III) Complexes.- c) Chloranilie Acid Methods.- d) Molybdenum Blue Methods.- D. Polarographic Methods.- E. Direct Electrometric Methods.- F. Radiometric Methods.- G. Catalytic Methods.- H. Determination of Elemental Fluorine.- VI. The Determination of Common Elements in Organic Fluorine Compounds.- A. Carbon, Hydrogen and Nitrogen.- B. Other Halogens, Sulfur and Phosphorus.- References.- 2: Effect of Inorganic Fluoride on Enzymes.- I. General Introduction.- II. Enzymes, Inhibited by Fluoride, Requiring Metal Ions, and Whose Inhibition is Enhanced by Phosphate.- A. Enolase.- B. Phosphoglucomutase.- C. Lecithinase (from Clostridium welchii).- D. Succinic Dehydrogenase.- III. Enzymes, Inhibited by Fluoride, Requiring Divalent Metal Ions.- A. Phosphatases.- 1. Acid Phosphatases.- 2. Alkaline Phosphatases.- B. Pyrophosphatases.- 1. Acid Pyrophosphatases.- 2. Alkaline Pyrophosphatases.- C. Kinases.- D. General.- 1. Cholinesterase.- 2. Glutamine Synthetase.- 3. Alcohol Dehydrogenase (Liver).- 4. ?-Amylase (Ca++-activated).- 5. Comments on Non-Inhibition by Fluoride of some Enzymes Activated by Divalent Metals.- IV. Enzymes Inhibited by Fluoride; No Requirement for Metal Ions Demonstrated.- A. Liver Esterase.- B. 5'-Adenylic Acid Deaminase.- C. Phosphoglycerate Mutase.- D. Hydrazidase.- V. Enzymes, Inhibited by Fluoride, Containing Trivalent Metal Ions.- A. Catalase.- B. Peroxidase.- VI. Concluding Comments.- References.- 3: Changes in Cell Function Due to Inorganic Fluoride.- I. Introduction.- II. Effect of Fluoride on Metabolic Pathways.- A. Outline of Intermediary Metabolism.- B. Glycolysis.- C. Pyruvate Metabolism and Oxidation in the Tricarboxylic Acid Cycle.- D. Oxidative Phosphorylation.- E. Respiration.- F. Protein Synthesis.- G. The Response of Tissues to Hormones.- H. Fat Metabolism in Adipose Tissue.- I. Lipases.- III. Effects of Fluoride on Physical Activity of Cells.- A. Movement.- 1. Motility.- 2. Phagocytosis.- 3. Contractility.- B. Transport Across Cell Membranes.- 1. Intestinal Epithelium.- 2. Non-Polar Cells.- IV. Effects of Fluoride on the Growth and Development of Cells in Tissue Culture.- V. Concluding Remarks.- References.- 4: Pharmacology of Sodium Fluoride.- I. Introduction.- II. Effect of Sodium Fluoride on Blood Pressure and the Heart.- A. Hypotensive Activity of Fluoride.- B. Pressor Effect of Fluoride.- C. Stimulatory Effect of Sodium Fluoride on Isolated Heart Preparations.- III. Effect of Sodium Fluoride on the Gut.- A. Effect of Fluoride on the Gut, in Vivo.- B. Effect of Fluoride on Dog Gut, in Vitro.- IV. Effect of Sodium Fluoride on Respiration.- V. Summary and Conclusions.- References.- 5: Fluoroamino Acids and Microorganisms.- I. Introduction.- II. Fluoroamino Acids and Cellular Microorganisms.- A. General Toxicity and Effects on Growing Cells.- B. Incorporation of Fluoroamino Acids into Proteins.- C. Effects of Fluoroamino Acids on Specific Cell Functions.- 1. Cell Division.- 2. Motility.- 3. Capsule Formation.- 4. Regulation of Enzyme Synthesis and Activity.- 5. Transport Systems.- 6. Bacterial Sporogenesis.- 7. Respiration and Photosynthesis.- 8. Ribosome Synthesis.- 9. Antibiotic Production.- 10. Maintenance of Diploid State in Fungi.- 11. Virus and Bacteriocin Production.- D. Catabolism of Fluoroamino Acids by Bacteria.- E. Bacterial Adaptation to Fluoroamino Acids.- 1. Physiologic Adaptation.- 2. Amino Acid-Secreting Mutants.- 3. Mutants with Altered Transport Systems.- 4. Mutants with Altered Amino Acyl-tRNA Synthetases.- 5. Mutants with Altered Ribosomes.- References.- 6: Fluorine-Containing Steroids.- I. Introduction.- II. Fluoro Steroids with Respect to Glucogenic, Anti-Inflammatory and Mineralocorticoid Effect.- A. The 9?-Fluoro-Substitution in.- 1. Cortisol.- 2. ?1-Cortisol (Prednisolone).- 3. ?6-Cortisol.- 4. Other Pregnane Derivatives.- B. Fluorination at other Positions and in Combination with 9?-Fluoro.- 1. In Cortisone, Cortisol, Prednisone or Prednisolone.- a) 2?-Fluoro.- b) 4-Fluoro.- c) 6? -Fluoro and 6?,9? -Difluoro.- d) 15?-Fluoro and 9?,15?-Difluoro.- e) 16? -Fluoro, 9?,16?-Difluoro, 6?,16? -Difluoro and 6?,9?,16? -Trifluoro.- f) 16?-fluoro and 9?,16?-Difluoro.- 2. In other Pregnane Derivatives.- a) 1l?-Fluoro.- b) 12? -Fluoro.- c) 17? -Fluoro.- d) 21-Fluoro.- e) Fluorine in 16?,17? -Ketal.- C. Other Groups in.- 1. 9? -Fluorocortisol and 9?-Fluoroprednisolone.- a) 1-Hydroxy.- b) 2? -Methyl.- c) 4-Methyl and 4-Ethyl.- d) 6? - and 6?-Chloro.- e) 6? -Fluoromethyl.- f) 6? -Methoxy.- g) 6? -Methyl.- h) 7? -Acetylthio.- i) 16?-Acetoxy.- j) 16?-Chloro.- k) 16? -Ethyl.- 1) 16? -1: Methods of Analysis for Fluorine.- I. Introduction.- II. Methods of Sample Preparation.- A. Organic Compounds.- 1. The Oxygen-Flask Method.- Procedure for Oxygen-Flask Combustion.- 2. Fusion with Alkali Metals.- Procedure for Alkali Metal Fusion.- 3. Reduction with Alkali Metal in Organic Solvents.- 4. Wickbold Oxyhydrogen Flame Method.- B. Inorganic Samples.- C. Agricultural and Food Samples.- D. Miscellaneous Samples.- III. Methods of Separation.- A. Separation of Fluorosilicic Acid by Distillation.- B. Separation by Pyrohydrolysis.- C. Separation by Diffusion.- D. Separation by Ion-exchange.- E. Chromatographic Separation on Paper and Thin Layers.- F. Other Methods of Separation.- IV. The Detection of Fluoride.- Procedure for the 8-Hydroxyquinoline Test.- V. The Determination of Fluoride.- A. Gravimetric Methods.- 1. Precipitation as Lead Chlorofluoride.- a) Recommended Lead Chlorofluoride Procedure.- ?) Reagents.- ?) Procedure.- 2. Precipitation as Calcium Fluoride.- B. Titrimetric Methods.- 1. Titration with Thorium Solution.- a) Interferences.- b) Direct Titration Procedure.- c) Back-Titration Procedure.- 2. Titration with Aluminum Solution.- 3. Acid-Base Titration of Hydrofluoric Acid.- 4. Titration with Rare Earth Solutions.- 5. Other Titrimetric Methods.- a) Titration with Calcium Solutions.- b) Titrations based on Lead Halofluoride Formation.- c) Titration with Iron(III) Solutions.- d) Titrations based on Fluorosilicic Acid.- C. Colorimetric Methods.- 1. The Alizarin Fluorine Blue Methods.- a) Recommended Lanthanum-Alizarin Fluorine Blue Procedure.- ?) Reagents.- ?) Calibration Graph.- 2. The Bleaching of Zirconium-Dye Complexes.- a) Recommended Zirconium-Eriochrome Cyanine R Procedure.- ?) Reagents.- ?) Calibration Graph.- 3. The Bleaching of Thorium-Dye Complexes.- 4. The Bleaching of Aluminum-Dye Complexes.- 5. Other Colorimetric Methods.- a) Titanium(IV) Complexes.- b) Iron(III) Complexes.- c) Chloranilie Acid Methods.- d) Molybdenum Blue Methods.- D. Polarographic Methods.- E. Direct Electrometric Methods.- F. Radiometric Methods.- G. Catalytic Methods.- H. Determination of Elemental Fluorine.- VI. The Determination of Common Elements in Organic Fluorine Compounds.- A. Carbon, Hydrogen and Nitrogen.- B. Other Halogens, Sulfur and Phosphorus.- References.- 2: Effect of Inorganic Fluoride on Enzymes.- I. General Introduction.- II. Enzymes, Inhibited by Fluoride, Requiring Metal Ions, and Whose Inhibition is Enhanced by Phosphate.- A. Enolase.- B. Phosphoglucomutase.- C. Lecithinase (from Clostridium welchii).- D. Succinic Dehydrogenase.- III. Enzymes, Inhibited by Fluoride, Requiring Divalent Metal Ions.- A. Phosphatases.- 1. Acid Phosphatases.- 2. Alkaline Phosphatases.- B. Pyrophosphatases.- 1. Acid Pyrophosphatases.- 2. Alkaline Pyrophosphatases.- C. Kinases.- D. General.- 1. Cholinesterase.- 2. Glutamine Synthetase.- 3. Alcohol Dehydrogenase (Liver).- 4. ?-Amylase (Ca++-activated).- 5. Comments on Non-Inhibition by Fluoride of some Enzymes Activated by Divalent Metals.- IV. Enzymes Inhibited by Fluoride; No Requirement for Metal Ions Demonstrated.- A. Liver Esterase.- B. 5'-Adenylic Acid Deaminase.- C. Phosphoglycerate Mutase.- D. Hydrazidase.- V. Enzymes, Inhibited by Fluoride, Containing Trivalent Metal Ions.- A. Catalase.- B. Peroxidase.- VI. Concluding Comments.- References.- 3: Changes in Cell Function Due to Inorganic Fluoride.- I. Introduction.- II. Effect of Fluoride on Metabolic Pathways.- A. Outline of Intermediary Metabolism.- B. Glycolysis.- C. Pyruvate Metabolism and Oxidation in the Tricarboxylic Acid Cycle.- D. Oxidative Phosphorylation.- E. Respiration.- F. Protein Synthesis.- G. The Response of Tissues to Hormones.- H. Fat Metabolism in Adipose Tissue.- I. Lipases.- III. Effects of Fluoride on Physical Activity of Cells.- A. Movement.- 1. Motility.- 2. Phagocytosis.- 3. Contractility.- B. Transport Across Cell Membranes.- 1. Intestinal Epithelium.- 2. Non-Polar Cells.- IV. Effects of Fluoride on the Growth and Development of Cells in Tissue Culture.- V. Concluding Remarks.- References.- 4: Pharmacology of Sodium Fluoride.- I. Introduction.- II. Effect of Sodium Fluoride on Blood Pressure and the Heart.- A. Hypotensive Activity of Fluoride.- B. Pressor Effect of Fluoride.- C. Stimulatory Effect of Sodium Fluoride on Isolated Heart Preparations.- III. Effect of Sodium Fluoride on the Gut.- A. Effect of Fluoride on the Gut, in Vivo.- B. Effect of Fluoride on Dog Gut, in Vitro.- IV. Effect of Sodium Fluoride on Respiration.- V. Summary and Conclusions.- References.- 5: Fluoroamino Acids and Microorganisms.- I. Introduction.- II. Fluoroamino Acids and Cellular Microorganisms.- A. General Toxicity and Effects on Growing Cells.- B. Incorporation of Fluoroamino Acids into Proteins.- C. Effects of Fluoroamino Acids on Specific Cell Functions.- 1. Cell Division.- 2. Motility.- 3. Capsule Formation.- 4. Regulation of Enzyme Synthesis and Activity.- 5. Transport Systems.- 6. Bacterial Sporogenesis.- 7. Respiration and Photosynthesis.- 8. Ribosome Synthesis.- 9. Antibiotic Production.- 10. Maintenance of Diploid State in Fungi.- 11. Virus and Bacteriocin Production.- D. Catabolism of Fluoroamino Acids by Bacteria.- E. Bacterial Adaptation to Fluoroamino Acids.- 1. Physiologic Adaptation.- 2. Amino Acid-Secreting Mutants.- 3. Mutants with Altered Transport Systems.- 4. Mutants with Altered Amino Acyl-tRNA Synthetases.- 5. Mutants with Altered Ribosomes.- References.- 6: Fluorine-Containing Steroids.- I. Introduction.- II. Fluoro Steroids with Respect to Glucogenic, Anti-Inflammatory and Mineralocorticoid Effect.- A. The 9?-Fluoro-Substitution in.- 1. Cortisol.- 2. ?1-Cortisol (Prednisolone).- 3. ?6-Cortisol.- 4. Other Pregnane Derivatives.- B. Fluorination at other Positions and in Combination with 9?-Fluoro.- 1. In Cortisone, Cortisol, Prednisone or Prednisolone.- a) 2?-Fluoro.- b) 4-Fluoro.- c) 6? -Fluoro and 6?,9? -Difluoro.- d) 15?-Fluoro and 9?,15?-Difluoro.- e) 16? -Fluoro, 9?,16?-Difluoro, 6?,16? -Difluoro and 6?,9?,16? -Trifluoro.- f) 16?-fluoro and 9?,16?-Difluoro.- 2. In other Pregnane Derivatives.- a) 1l?-Fluoro.- b) 12? -Fluoro.- c) 17? -Fluoro.- d) 21-Fluoro.- e) Fluorine in 16?,17? -Ketal.- C. Other Groups in.- 1. 9? -Fluorocortisol and 9?-Fluoroprednisolone.- a) 1-Hydroxy.- b) 2? -Methyl.- c) 4-Methyl and 4-Ethyl.- d) 6? - and 6?-Chloro.- e) 6? -Fluoromethyl.- f) 6? -Methoxy.- g) 6? -Methyl.- h) 7? -Acetylthio.- i) 16?-Acetoxy.- j) 16?-Chloro.- k) 16? -Ethyl.- 1) 16? -Fluoromethyl.- m) 16? -Hydroxy.- n) 116?,17?-Ketal.- o) 16? -Methoxy.- p) 16? - and 16?-Methyl.- q) 16-Methylene or ?15-16-Methyl.- r) 16?, 17?-Orthoesters (Cyclic).- s) 21-Methyl.- 2. Other 9?-Fluoropregnane Derivatives.- a) 6?-Methyl.- b) 16? -Chloro, Nitrogen and Sulfur Containing Groups.- e) 16? -Hydroxy and Acetonide.- d) 16? -Methyl.- e) 17?,21-Epoxy.- f) 21-Chloro, 16? -Hydroxy and Acetonide.- g) 21-Chloro, 16? -Hydroxy,2? -Methyl, Acetonide.- D. With More than one Change in the 9? -Fluorocortisol or 9? -Fluoroprednisolone Molecule.- 1. ?6, 16? -Hydroxy.- 2. 6?,7? -Dihydroxy.- 3. 6?,16? -Dimethyl.- 4. 6? -Fluoro, 16? -Hydroxy and Acetonide.- 5. 6? -Fluoro, 16? -Methyl.- 6. 6? -Fluoro, 21-Methyl.- 7. 6-Formyl, 3-Enol Ether, 16? -Hydroxy, Acetonide.- 8. 6? -Methyl, 16? -Hydroxy and Acetonide.- 9. ll?-Acetoxy, 16? -Hydroxy.- 10. 16? -Methyl, 17? -Methoxy.- 11. 17,20:20,21-Bismethylenedioxy.- 12. 20-Ketal Derivatives.- 13. 21-Sugar Derivatives, 16? -Hydroxy.- 14. 21-Tetrahydropyranyl Ether, 16? -Hydroxy, Acetonide.- E. Pyrazol Ring Attached to Ring A.- F. Other Groups in 6a-Fluoro Compounds without 9a-Fluoro Substitution.- 1. 6? -Fluoro, 2-Methyl, 16? -Hydroxy, Acetonide, ?1.- 2. 6? -Fluoro, 16? -Hydroxy, and 6? -Fluoro, 16? -Methyl.- 3. 6? -Fluoro, 16? -Hydroxy, ?8 and Acetonide.- 4. 6a-Fluoro, 3?-Acetoxy, 16? -Hydroxy Acetonide.- G. Analytical Problems in Studying Fluorosteroids.- 1. General Aspects.- 2. Extraction.- 3. Fluorosteroid Color Reaction.- 4. Determination in Urine as 17-Ketosteroids.- 5. Paper and Column Chromatography.- 6. Preparation of Tritium-Labeled Triamcinolone.- 7. Isomerization.- H. Metabolism.- 1. Absorption.- a) Intestinal.- b) Percutaneous.- c) Intra-Articular.- 2. In Vitro Studies.- a) Liver Slices or Homogenates.- b) Metabolism by Micro-Organisms.- c) Adrenal Metabolism of 9? -Fluoroandrostenedione.- 3. Plasma Protein Binding.- 4. In Vivo Studies.- a) Plasma Half-Life and Tissue Distribution.- b) Excretion of Metabolites.- I. Biological Effects of Fluorocorticoids.- 1. Microbiological Systems.- a) Growth Rate Stimulation.- b) Growth Rate Inhibition.- c) Enzyme Activity - Alkaline Phosphatase.- 2. Isolated Systems in Vitro.- a) Frog-Skin Sacs.- b) Frog Skin, Short Circuited.- c) Perfused Rabbit Heart.- d) Cat Papillary Muscle.- 3. Effects in Animals.- a) Liver Enzymes.- b) Thymus Enzymes.- c) Skin Enzymes.- d) Skin Composition.- e) Kidney. Infused Renal Artery.- f) Effects in Whole Animals.- g) Toxicology.- 4. Effects in Man.- a) Extrapolation from Animal Bioassays to Man.- b) Use of Corticosteroids.- c) Adrenal Suppression.- d) Side Effects of Therapeutic Doses.- e) Topical Effectiveness of Fluorosteroids.- III. Fluoro-Steroids with Respect to Gestagenic, Anti-Androgenic, Anti-Estrogenic, Anti-Ovulatory, and Anti-Gonadotrophic Effects.- A. The 9?-Fluoro-Substitution in.- 1. Progesterone and 11-Oxygenated Progesterone.- 2. 17? -Acetoxyprogesterone, 11-Oxygenated.- 3. ll?-Hydroxy-17?-Methyltestosterone.- B. Fluorination at other Positions.- 1. In Progesterone, and Its 9? -Halogenated and 11-Oxygenated Derivatives.- a) 2? -Fluoro.- b) 6? -Fluoro.- c) 6,6-Difluoro.- d) 11?-Fluoro.- e) 12? -Fluoro.- f) 17? -Fluoro.- g) 21-Fluoro.- h) 21,21-Difluoro.- i) 21,21,21-Trifluoro.- 2.In 17? -Acetoxyprogesterone.- a) 6? - and 6?-Fluoro, ?1 and ?6.- b) 21-Fluoro.- C. Other Groups in Combination with Fluorination in the Progesterone Molecule.- 1. 4-Fluoro, 6?, 16? -Dimethyl and 4,4-Difluoro Derivatives.- 2. 6? - and 6?-Fluoro, 16?,17? -Dihydroxy and Ketals.- 3. 6? -Fluoro, 16? -Methyl.- 4. 6? -Fluoro, 17? -Methyl, 6-Fluoro, 17? -Ethyl, ?6 and 6?, 21-Difluoro, 17? -Methyl.- 5. 6? -Trifmoromethyl, 17? -Acetoxy.- 6. 21-Fluoro, 6-Chloro, 17? -Aeetoxy, ?6.- 7. 21-Fluoro, 6a-Methyl, 17? -Acetoxy and ?6.- 8. 21-Fluoro, 6?, 16? -Dimethyl, 17? -Hydroxy and ?6.- 9. 21-Fluoro, 17? -Methyl, 6-Methyl and 6-Chloro, ?1 and ?6.- D. Fluorination in.- 1. Ethisterone, 19-Norethisterone and Derivatives thereof.- a) 5? -Fluoro, Dihydro, 19-Nor-10?-Hydroxy.- b) 6? -Fluoro.- c) 10?-Fluoro-19-Nor.- d) 16? -Fluoro, 17? - and 17?-Chloroethinyl.- 2. 9?,10? -Pregnanes -1: Methods of Analysis for Fluorine.- I. Introduction.- II. Methods of Sample Preparation.- A. Organic Compounds.- 1. The Oxygen-Flask Method.- Procedure for Oxygen-Flask Combustion.- 2. Fusion with Alkali Metals.- Procedure for Alkali Metal Fusion.- 3. Reduction with Alkali Metal in Organic Solvents.- 4. Wickbold Oxyhydrogen Flame Method.- B. Inorganic Samples.- C. Agricultural and Food Samples.- D. Miscellaneous Samples.- III. Methods of Separation.- A. Separation of Fluorosilicic Acid by Distillation.- B. Separation by Pyrohydrolysis.- C. Separation by Diffusion.- D. Separation by Ion-exchange.- E. Chromatographic Separation on Paper and Thin Layers.- F. Other Methods of Separation.- IV. The Detection of Fluoride.- Procedure for the 8-Hydroxyquinoline Test.- V. The Determination of Fluoride.- A. Gravimetric Methods.- 1. Precipitation as Lead Chlorofluoride.- a) Recommended Lead Chlorofluoride Procedure.- ?) Reagents.- ?) Procedure.- 2. Precipitation as Calcium Fluoride.- B. Titrimetric Methods.- 1. Titration with Thorium Solution.- a) Interferences.- b) Direct Titration Procedure.- c) Back-Titration Procedure.- 2. Titration with Aluminum Solution.- 3. Acid-Base Titration of Hydrofluoric Acid.- 4. Titration with Rare Earth Solutions.- 5. Other Titrimetric Methods.- a) Titration with Calcium Solutions.- b) Titrations based on Lead Halofluoride Formation.- c) Titration with Iron(III) Solutions.- d) Titrations based on Fluorosilicic Acid.- C. Colorimetric Methods.- 1. The Alizarin Fluorine Blue Methods.- a) Recommended Lanthanum-Alizarin Fluorine Blue Procedure.- ?) Reagents.- ?) Calibration Graph.- 2. The Bleaching of Zirconium-Dye Complexes.- a) Recommended Zirconium-Eriochrome Cyanine R Procedure.- ?) Reagents.- ?) Calibration Graph.- 3. The Bleaching of Thorium-Dye Complexes.- 4. The Bleaching of Aluminum-Dye Complexes.- 5. Other Colorimetric Methods.- a) Titanium(IV) Complexes.- b) Iron(III) Complexes.- c) Chloranilie Acid Methods.- d) Molybdenum Blue Methods.- D. Polarographic Methods.- E. Direct Electrometric Methods.- F. Radiometric Methods.- G. Catalytic Methods.- H. Determination of Elemental Fluorine.- VI. The Determination of Common Elements in Organic Fluorine Compounds.- A. Carbon, Hydrogen and Nitrogen.- B. Other Halogens, Sulfur and Phosphorus.- References.- 2: Effect of Inorganic Fluoride on Enzymes.- I. General Introduction.- II. Enzymes, Inhibited by Fluoride, Requiring Metal Ions, and Whose Inhibition is Enhanced by Phosphate.- A. Enolase.- B. Phosphoglucomutase.- C. Lecithinase (from Clostridium welchii).- D. Succinic Dehydrogenase.- III. Enzymes, Inhibited by Fluoride, Requiring Divalent Metal Ions.- A. Phosphatases.- 1. Acid Phosphatases.- 2. Alkaline Phosphatases.- B. Pyrophosphatases.- 1. Acid Pyrophosphatases.- 2. Alkaline Pyrophosphatases.- C. Kinases.- D. General.- 1. Cholinesterase.- 2. Glutamine Synthetase.- 3. Alcohol Dehydrogenase (Liver).- 4. ?-Amylase (Ca++-activated).- 5. Comments on Non-Inhibition by Fluoride of some Enzymes Activated by Divalent Metals.- IV. Enzymes Inhibited by Fluoride; No Requirement for Metal Ions Demonstrated.- A. Liver Esterase.- B. 5'-Adenylic Acid Deaminase.- C. Phosphoglycerate Mutase.- D. Hydrazidase.- V. Enzymes, Inhibited by Fluoride, Containing Trivalent Metal Ions.- A. Catalase.- B. Peroxidase.- VI. Concluding Comments.- References.- 3: Changes in Cell Function Due to Inorganic Fluoride.- I. Introduction.- II. Effect of Fluoride on Metabolic Pathways.- A. Outline of Intermediary Metabolism.- B. Glycolysis.- C. Pyruvate Metabolism and Oxidation in the Tricarboxylic Acid Cycle.- D. Oxidative Phosphorylation.- E. Respiration.- F. Protein Synthesis.- G. The Response of Tissues to Hormones.- H. Fat Metabolism in Adipose Tissue.- I. Lipases.- III. Effects of Fluoride on Physical Activity of Cells.- A. Movement.- 1. Motility.- 2. Phagocytosis.- 3. Contractility.- B. Transport Across Cell Membranes.- 1. Intestinal Epithelium.- 2. Non-Polar Cells.- IV. Effects of Fluoride on the Growth and Development of Cells in Tissue Culture.- V. Concluding Remarks.- References.- 4: Pharmacology of Sodium Fluoride.- I. Introduction.- II. Effect of Sodium Fluoride on Blood Pressure and the Heart.- A. Hypotensive Activity of Fluoride.- B. Pressor Effect of Fluoride.- C. Stimulatory Effect of Sodium Fluoride on Isolated Heart Preparations.- III. Effect of Sodium Fluoride on the Gut.- A. Effect of Fluoride on the Gut, in Vivo.- B. Effect of Fluoride on Dog Gut, in Vitro.- IV. Effect of Sodium Fluoride on Respiration.- V. Summary and Conclusions.- References.- 5: Fluoroamino Acids and Microorganisms.- I. Introduction.- II. Fluoroamino Acids and Cellular Microorganisms.- A. General Toxicity and Effects on Growing Cells.- B. Incorporation of Fluoroamino Acids into Proteins.- C. Effects of Fluoroamino Acids on Specific Cell Functions.- 1. Cell Division.- 2. Motility.- 3. Capsule Formation.- 4. Regulation of Enzyme Synthesis and Activity.- 5. Transport Systems.- 6. Bacterial Sporogenesis.- 7. Respiration and Photosynthesis.- 8. Ribosome Synthesis.- 9. Antibiotic Production.- 10. Maintenance of Diploid State in Fungi.- 11. Virus and Bacteriocin Production.- D. Catabolism of Fluoroamino Acids by Bacteria.- E. Bacterial Adaptation to Fluoroamino Acids.- 1. Physiologic Adaptation.- 2. Amino Acid-Secreting Mutants.- 3. Mutants with Altered Transport Systems.- 4. Mutants with Altered Amino Acyl-tRNA Synthetases.- 5. Mutants with Altered Ribosomes.- References.- 6: Fluorine-Containing Steroids.- I. Introduction.- II. Fluoro Steroids with Respect to Glucogenic, Anti-Inflammatory and Mineralocorticoid Effect.- A. The 9?-Fluoro-Substitution in.- 1. Cortisol.- 2. ?1-Cortisol (Prednisolone).- 3. ?6-Cortisol.- 4. Other Pregnane Derivatives.- B. Fluorination at other Positions and in Combination with 9?-Fluoro.- 1. In Cortisone, Cortisol, Prednisone or Prednisolone.- a) 2?-Fluoro.- b) 4-Fluoro.- c) 6? -Fluoro and 6?,9? -Difluoro.- d) 15?-Fluoro and 9?,15?-Difluoro.- e) 16? -Fluoro, 9?,16?-Difluoro, 6?,16? -Difluoro and 6?,9?,16? -Trifluoro.- f) 16?-fluoro and 9?,16?-Difluoro.- 2. In other Pregnane Derivatives.- a) 1l?-Fluoro.- b) 12? -Fluoro.- c) 17? -Fluoro.- d) 21-Fluoro.- e) Fluorine in 16?,17? -Ketal.- C. Other Groups in.- 1. 9? -Fluorocortisol and 9?-Fluoroprednisolone.- a) 1-Hydroxy.- b) 2? -Methyl.- c) 4-Methyl and 4-Ethyl.- d) 6? - and 6?-Chloro.- e) 6? -Fluoromethyl.- f) 6? -Methoxy.- g) 6? -Methyl.- h) 7? -Acetylthio.- i) 16?-Acetoxy.- j) 16?-Chloro.- k) 16? -Ethyl.- 1) 16? -Fluoromethyl.- m) 16? -Hydroxy.- n) 116?,17?-Ketal.- o) 16? -Methoxy.- p) 16? - and 16?-Methyl.- q) 16-Methylene or ?15-16-Methyl.- r) 16?, 17?-Orthoesters (Cyclic).- s) 21-Methyl.- 2. Other 9?-Fluoropregnane Derivatives.- a) 6?-Methyl.- b) 16? -Chloro, Nitrogen and Sulfur Containing Groups.- e) 16? -Hydroxy and Acetonide.- d) 16? -Methyl.- e) 17?,21-Epoxy.- f) 21-Chloro, 16? -Hydroxy and Acetonide.- g) 21-Chloro, 16? -Hydroxy,2? -Methyl, Acetonide.- D. With More than one Change in the 9? -Fluorocortisol or 9? -Fluoroprednisolone Molecule.- 1. ?6, 16? -Hydroxy.- 2. 6?,7? -Dihydroxy.- 3. 6?,16? -Dimethyl.- 4. 6? -Fluoro, 16? -Hydroxy and Acetonide.- 5. 6? -Fluoro, 16? -Methyl.- 6. 6? -Fluoro, 21-Methyl.- 7. 6-Formyl, 3-Enol Ether, 16? -Hydroxy, Acetonide.- 8. 6? -Methyl, 16? -Hydroxy and Acetonide.- 9. ll?-Acetoxy, 16? -Hydroxy.- 10. 16? -Methyl, 17? -Methoxy.- 11. 17,20:20,21-Bismethylenedioxy.- 12. 20-Ketal Derivatives.- 13. 21-Sugar Derivatives, 16? -Hydroxy.- 14. 21-Tetrahydropyranyl Ether, 16? -Hydroxy, Acetonide.- E. Pyrazol Ring Attached to Ring A.- F. Other Groups in 6a-Fluoro Compounds without 9a-Fluoro Substitution.- 1. 6? -Fluoro, 2-Methyl, 16? -Hydroxy, Acetonide, ?1.- 2. 6? -Fluoro, 16? -Hydroxy, and 6? -Fluoro, 16? -Methyl.- 3. 6? -Fluoro, 16? -Hydroxy, ?8 and Acetonide.- 4. 6a-Fluoro, 3?-Acetoxy, 16? -Hydroxy Acetonide.- G. Analytical Problems in Studying Fluorosteroids.- 1. General Aspects.- 2. Extraction.- 3. Fluorosteroid Color Reaction.- 4. Determination in Urine as 17-Ketosteroids.- 5. Paper and Column Chromatography.- 6. Preparation of Tritium-Labeled Triamcinolone.- 7. Isomerization.- H. Metabolism.- 1. Absorption.- a) Intestinal.- b) Percutaneous.- c) Intra-Articular.- 2. In Vitro Studies.- a) Liver Slices or Homogenates.- b) Metabolism by Micro-Organisms.- c) Adrenal Metabolism of 9? -Fluoroandrostenedione.- 3. Plasma Protein Binding.- 4. In Vivo Studies.- a) Plasma Half-Life and Tissue Distribution.- b) Excretion of Metabolites.- I. Biological Effects of Fluorocorticoids.- 1. Microbiological Systems.- a) Growth Rate Stimulation.- b) Growth Rate Inhibition.- c) Enzyme Activity - Alkaline Phosphatase.- 2. Isolated Systems in Vitro.- a) Frog-Skin Sacs.- b) Frog Skin, Short Circuited.- c) Perfused Rabbit Heart.- d) Cat Papillary Muscle.- 3. Effects in Animals.- a) Liver Enzymes.- b) Thymus Enzymes.- c) Skin Enzymes.- d) Skin Composition.- e) Kidney. Infused Renal Artery.- f) Effects in Whole Animals.- g) Toxicology.- 4. Effects in Man.- a) Extrapolation from Animal Bioassays to Man.- b) Use of Corticosteroids.- c) Adrenal Suppression.- d) Side Effects of Therapeutic Doses.- e) Topical Effectiveness of Fluorosteroids.- III. Fluoro-Steroids with Respect to Gestagenic, Anti-Androgenic, Anti-Estrogenic, Anti-Ovulatory, and Anti-Gonadotrophic Effects.- A. The 9?-Fluoro-Substitution in.- 1. Progesterone and 11-Oxygenated Progesterone.- 2. 17? -Acetoxyprogesterone, 11-Oxygenated.- 3. ll?-Hydroxy-17?-Methyltestosterone.- B. Fluorination at other Positions.- 1. In Progesterone, and Its 9? -Halogenated and 11-Oxygenated Derivatives.- a) 2? -Fluoro.- b) 6? -Fluoro.- c) 6,6-Difluoro.- d) 11?-Fluoro.- e) 12? -Fluoro.- f) 17? -Fluoro.- g) 21-Fluoro.- h) 21,21-Difluoro.- i) 21,21,21-Trifluoro.- 2.In 17? -Acetoxyprogesterone.- a) 6? - and 6?-Fluoro, ?1 and ?6.- b) 21-Fluoro.- C. Other Groups in Combination with Fluorination in the Progesterone Molecule.- 1. 4-Fluoro, 6?, 16? -Dimethyl and 4,4-Difluoro Derivatives.- 2. 6? - and 6?-Fluoro, 16?,17? -Dihydroxy and Ketals.- 3. 6? -Fluoro, 16? -Methyl.- 4. 6? -Fluoro, 17? -Methyl, 6-Fluoro, 17? -Ethyl, ?6 and 6?, 21-Difluoro, 17? -Methyl.- 5. 6? -Trifmoromethyl, 17? -Acetoxy.- 6. 21-Fluoro, 6-Chloro, 17? -Aeetoxy, ?6.- 7. 21-Fluoro, 6a-Methyl, 17? -Acetoxy and ?6.- 8. 21-Fluoro, 6?, 16? -Dimethyl, 17? -Hydroxy and ?6.- 9. 21-Fluoro, 17? -Methyl, 6-Methyl and 6-Chloro, ?1 and ?6.- D. Fluorination in.- 1. Ethisterone, 19-Norethisterone and Derivatives thereof.- a) 5? -Fluoro, Dihydro, 19-Nor-10?-Hydroxy.- b) 6? -Fluoro.- c) 10?-Fluoro-19-Nor.- d) 16? -Fluoro, 17? - and 17?-Chloroethinyl.- 2. 9?,10? -Pregnanes - 6-Fluoro, ?6 and 17? -Acetoxy.- E. Miscellaneous.- F. Biological Effects of Fluoroprogestational Steroids.- 1. Anti-Estrogenic Action.- 2. Anti-Gonadotropin Activity.- 3. Anti-Ovulatory Activity.- IV.Fluoro-Steroids with Respect to Androgenic, Anabolic, Anti-Androgenic, Anti-Tumor and Anti-Gonadotropic Effect.- A. The 9? -Fluoro Substitution in.- 1. 11?-Hydroxy-?4-Androstene-3,17-Dione.- 2. 17? -Methyltestosterone, 11-Oxygenated.- B. Muorination at other Positions in ?4-Androstene-3-one or Dihydro Compounds.- 1. 2?- and 2?-Muoro.- 2. 4-Fluoro.- 3. 6?- and 6? Fluoro.- 4. 6,6-Difluoro.- 5. 16? - and 16?-Fluoro and 16,16-Difluoro.- C. Other Groups in ?4-Androstene-3-one or Dihydro Compounds in Combination with Fluorination.- 1. 9? -Fluoro, 11?-Hydroxy, 7? -Acetylthio.- 2. 9? -Fluoro, 11?-Hydroxy, 16? -Methyl.- 3. ll?-Fluoro, 9? -Halogen.- 4. 16? -Fluoro, 16?-Methyl.- D.Fluorination in other Androstane-3-one Derivatives.- 1.19-Nor-Derivatives.- a) 4,4-Difluoro.- b) 5? -Fluoro, 10?-Hydroxy.- c) 10? -Fluoro.- 2. 9?, 10?.- 6-Fluoro, ?4,6.- E. Fluorination in Androstane Compounds without 3-Keto.- 1. In the Ring.- a) 3?-Fluoro.- b) 9?-Fluoro, 11? -Hydroxy, 3-Methylene.- 2. In Side Chain.- a) 2-Fluoromethyl and 2-Difluoromethyl, ?2.- b) 2?, 3? - and 2?, 3?-Difluoromethylene.- F. Miscellaneous.- G. In Vitro Metabolism.- H. Biological Effects of Fluoro Androgenic-Anabolic Steroids.- 1. Growth Stimulation in Man.- 2. Anti-Androgenic Action.- V. Fluoro-Steroids with Respect to Estrogenic, Hypocholesterolemic, Anti-Gonadotropic and Anti-Tumor Effects.- A. Fluorination in.- 1. Ring-A Aromatic Steroids.- a) 3-Fluoro.- b)4-Fluoro.- c) 16? -Fluoro, 16?-Cyano.- d) 16,16-Difluoro.- 2. 19-Norethisterone.- 10?-Fluoro.- 3. In Side Chain.- 17?-(2-Fluoroethyl)Ether.- VI. Fluoro Steroids with Respect to Anti-Mineralocorticoid Effect.- VII. Anti-Cancer Effects of Fluoro Steroids.- VIII. Structure-Activity Relationships and Influence of Fluorination.- IX. Other Fluoro-Steroids.- References.- 7: Biological Properties of Selected Fluorine-Containing Organic Compounds.- I. Introduction.- A. Preparation of Biologically Active Compounds of Fluorine.- B. Mechanisms of Action of Organically Bound Fluorine.- II. The Carbon-Fluorine Bond.- A. Physical Properties.- B. In Vivo Synthesis of the C-F Bond.- III. Metabolism of Organic Fluoroeompounds.- A. In Vivo Rupture of the C-F Bond.- 1. Microbial Cleavage of the C-F Bond.- a) Aliphatic Compounds.- b) Aromatic Compounds.- 2. Mammalian Cleavage of the C-F Bond.- a) Aliphatic Compounds.- i) Fluoroacetic acid.- ii) Halogenated Anesthetics.- iii) Fluorine-Containing Sugars.- iv) Fluoro-Oxaloacetate.- b) Aromatic Compounds.- i) Fluoronitrobenzenes.- ii) 4-Fluorophenylalanine.- iii) Acetanilides and Anilines.- iv) 4'-Fluoro-4-dimethylaminoazobenzene.- 3. Cleavage of the C-F Bond in Plants.- B. Biotransformations not Involving the C-F Bond.- 1. Bacterial Metabolism.- a) Fluoronicotinic Acids.- b) Fluorobenzoic Acids.- c) p-Fluorophenylalanine.- d) 6-Fluorotryptophan.- e) 3-Deoxy-3-Fluoro-D-Glucose.- 2. Mammalian Metabolism.- a) Fluorobenzene.- b) Fluorobenzoic Acids and Amides.- c) Fluorothiobenzoic Acids.- d) Trifluralin.- e) Fluorine-Substituted Amino Acids.- i) m-Fluorotyrosine.- ii) Fluorophenylalanines.- iii) 5-Fluorotryptophan.- f)Other Compounds.- IV. Biological Effects of Organic Compounds of Fluorine.- A. Effects of Amino Acid Analogues on Protein Synthesis and Enzyme Induction in Mammalian Systems.- 1. Growth.- 2. Incorporation into Protein.- 3. Effects on Amino Acid Transport.- 4. Effects on Activating Enzyme.- 5. Metabolism of Fluorine-Containing Amino Acid Analogues.- B. Effects of Organic Fluoro Compounds Upon Microorganisms.- C. Organic Fluoro Compounds in Experimental Cancer Studies.- 1. Anticancer Agents.- 2. Production of Experimental Cancers.- a) Derivatives of Dimethylaminoazobenzene.- b) Fluorinated Derivatives of 2-Acetylaminofluorene and Related Compounds.- c) Fluorinated Derivatives of 10-Methyl-1,2-Benzanthracene.- d) Fluorotricycloquinazoline.- D. Psychosedative Drugs.- 1. Phenothiazines.- a) Structure -#8212; 6-Fluoro, ?6 and 17? -Acetoxy.- E. Miscellaneous.- F. Biological Effects of Fluoroprogestational Steroids.- 1. Anti-Estrogenic Action.- 2. Anti-Gonadotropin Activity.- 3. Anti-Ovulatory Activity.- IV.Fluoro-Steroids with Respect to Androgenic, Anabolic, Anti-Androgenic, Anti-Tumor and Anti-Gonadotropic Effect.- A. The 9? -Fluoro Substitution in.- 1. 11?-Hydroxy-?4-Androstene-3,17-Dione.- 2. 17? -Methyltestosterone, 11-Oxygenated.- B. Muorination at other Positions in ?4-Androstene-3-one or Dihydro Compounds.- 1. 2?- and 2?-Muoro.- 2. 4-Fluoro.- 3. 6?- and 6? Fluoro.- 4. 6,6-Difluoro.- 5. 16? - and 16?-Fluoro and 16,16-Difluoro.- C. Other Groups in ?4-Androstene-3-one or Dihydro Compounds in Combination with Fluorination.- 1. 9? -Fluoro, 11?-Hydroxy, 7? -Acetylthio.- 2. 9? -Fluoro, 11?-Hydroxy, 16? -Methyl.- 3. ll?-Fluoro, 9? -Halogen.- 4. 16? -Fluoro, 16?-Methyl.- D.Fluorination in other Androstane-3-one Derivatives.- 1.19-Nor-Derivatives.- a) 4,4-Difluoro.- b) 5? -Fluoro, 10?-Hydroxy.- c) 10? -Fluoro.- 2. 9?, 10?.- 6-Fluoro, ?4,6.- E. Fluorination in Androstane Compounds without 3-Keto.- 1. In the Ring.- a) 3?-Fluoro.- b) 9?-Fluoro, 11? -Hydroxy, 3-Methylene.- 2. In Side Chain.- a) 2-Fluoromethyl and 2-Difluoromethyl, ?2.- b) 2?, 3? - and 2?, 3?-Difluoromethylene.- F. Miscellaneous.- G. In Vitro Metabolism.- H. Biological Effects of Fluoro Androgenic-Anabolic Steroids.- 1. Growth Stimulation in Man.- 2. Anti-Androgenic Action.- V. Fluoro-Steroids with Respect to Estrogenic, Hypocholesterolemic, Anti-Gonadotropic and Anti-Tumor Effects.- A. Fluorination in.- 1. Ring-A Aromatic Steroids.- a) 3-Fluoro.- b)4-Fluoro.- c) 16? -Fluoro, 16?-Cyano.- d) 16,16-Difluoro.- 2. 19-Norethisterone.- 10?-Fluoro.- 3. In Side Chain.- 17?-(2-Fluoroethyl)Ether.- VI. Fluoro Steroids with Respect to Anti-Mineralocorticoid Effect.- VII. Anti-Cancer Effects of Fluoro Steroids.- VIII. Structure-Activity Relationships and Influence of Fluorination.- IX. Other Fluoro-Steroids.- References.- 7: Biological Properties of Selected Fluorine-Containing Organic Compounds.- I. Introduction.- A. Preparation of Biologically Active Compounds of Fluorine.- B. Mechanisms of Action of Organically Bound Fluorine.- II. The Carbon-Fluorine Bond.- A. Physical Properties.- B. In Vivo Synthesis of the C-F Bond.- III. Metabolism of Organic Fluoroeompounds.- A. In Vivo Rupture of the C-F Bond.- 1. Microbial Cleavage of the C-F Bond.- a) Aliphatic Compounds.- b) Aromatic Compounds.- 2. Mammalian Cleavage of the C-F Bond.- a) Aliphatic Compounds.- i) Fluoroacetic acid.- ii) Halogenated Anesthetics.- iii) Fluorine-Containing Sugars.- iv) Fluoro-Oxaloacetate.- b) Aromatic Compounds.- i) Fluoronitrobenzenes.- ii) 4-Fluorophenylalanine.- iii) Acetanilides and Anilines.- iv) 4'-Fluoro-4-dimethylaminoazobenzene.- 3. Cleavage of the C-F Bond in Plants.- B. Biotransformations not Involving the C-F Bond.- 1. Bacterial Metabolism.- a) Fluoronicotinic Acids.- b) Fluorobenzoic Acids.- c) p-Fluorophenylalanine.- d) 6-Fluorotryptophan.- e) 3-Deoxy-3-Fluoro-D-Glucose.- 2. Mammalian Metabolism.- a) Fluorobenzene.- b) Fluorobenzoic Acids and Amides.- c) Fluorothiobenzoic Acids.- d) Trifluralin.- e) Fluorine-Substituted Amino Acids.- i) m-Fluorotyrosine.- ii) Fluorophenylalanines.- iii) 5-Fluorotryptophan.- f)Other Compounds.- IV. Biological Effects of Organic Compounds of Fluorine.- A. Effects of Amino Acid Analogues on Protein Synthesis and Enzyme Induction in Mammalian Systems.- 1. Growth.- 2. Incorporation into Protein.- 3. Effects on Amino Acid Transport.- 4. Effects on Activating Enzyme.- 5. Metabolism of Fluorine-Containing Amino Acid Analogues.- B. Effects of Organic Fluoro Compounds Upon Microorganisms.- C. Organic Fluoro Compounds in Experimental Cancer Studies.- 1. Anticancer Agents.- 2. Production of Experimental Cancers.- a) Derivatives of Dimethylaminoazobenzene.- b) Fluorinated Derivatives of 2-Acetylaminofluorene and Related Compounds.- c) Fluorinated Derivatives of 10-Methyl-1,2-Benzanthracene.- d) Fluorotricycloquinazoline.- D. Psychosedative Drugs.- 1. Phenothiazines.- a) Structure -1: Methods of Analysis for Fluorine.- I. Introduction.- II. Methods of Sample Preparation.- A. Organic Compounds.- 1. The Oxygen-Flask Method.- Procedure for Oxygen-Flask Combustion.- 2. Fusion with Alkali Metals.- Procedure for Alkali Metal Fusion.- 3. Reduction with Alkali Metal in Organic Solvents.- 4. Wickbold Oxyhydrogen Flame Method.- B. Inorganic Samples.- C. Agricultural and Food Samples.- D. Miscellaneous Samples.- III. Methods of Separation.- A. Separation of Fluorosilicic Acid by Distillation.- B. Separation by Pyrohydrolysis.- C. Separation by Diffusion.- D. Separation by Ion-exchange.- E. Chromatographic Separation on Paper and Thin Layers.- F. Other Methods of Separation.- IV. The Detection of Fluoride.- Procedure for the 8-Hydroxyquinoline Test.- V. The Determination of Fluoride.- A. Gravimetric Methods.- 1. Precipitation as Lead Chlorofluoride.- a) Recommended Lead Chlorofluoride Procedure.- ?) Reagents.- ?) Procedure.- 2. Precipitation as Calcium Fluoride.- B. Titrimetric Methods.- 1. Titration with Thorium Solution.- a) Interferences.- b) Direct Titration Procedure.- c) Back-Titration Procedure.- 2. Titration with Aluminum Solution.- 3. Acid-Base Titration of Hydrofluoric Acid.- 4. Titration with Rare Earth Solutions.- 5. Other Titrimetric Methods.- a) Titration with Calcium Solutions.- b) Titrations based on Lead Halofluoride Formation.- c) Titration with Iron(III) Solutions.- d) Titrations based on Fluorosilicic Acid.- C. Colorimetric Methods.- 1. The Alizarin Fluorine Blue Methods.- a) Recommended Lanthanum-Alizarin Fluorine Blue Procedure.- ?) Reagents.- ?) Calibration Graph.- 2. The Bleaching of Zirconium-Dye Complexes.- a) Recommended Zirconium-Eriochrome Cyanine R Procedure.- ?) Reagents.- ?) Calibration Graph.- 3. The Bleaching of Thorium-Dye Complexes.- 4. The Bleaching of Aluminum-Dye Complexes.- 5. Other Colorimetric Methods.- a) Titanium(IV) Complexes.- b) Iron(III) Complexes.- c) Chloranilie Acid Methods.- d) Molybdenum Blue Methods.- D. Polarographic Methods.- E. Direct Electrometric Methods.- F. Radiometric Methods.- G. Catalytic Methods.- H. Determination of Elemental Fluorine.- VI. The Determination of Common Elements in Organic Fluorine Compounds.- A. Carbon, Hydrogen and Nitrogen.- B. Other Halogens, Sulfur and Phosphorus.- References.- 2: Effect of Inorganic Fluoride on Enzymes.- I. General Introduction.- II. Enzymes, Inhibited by Fluoride, Requiring Metal Ions, and Whose Inhibition is Enhanced by Phosphate.- A. Enolase.- B. Phosphoglucomutase.- C. Lecithinase (from Clostridium welchii).- D. Succinic Dehydrogenase.- III. Enzymes, Inhibited by Fluoride, Requiring Divalent Metal Ions.- A. Phosphatases.- 1. Acid Phosphatases.- 2. Alkaline Phosphatases.- B. Pyrophosphatases.- 1. Acid Pyrophosphatases.- 2. Alkaline Pyrophosphatases.- C. Kinases.- D. General.- 1. Cholinesterase.- 2. Glutamine Synthetase.- 3. Alcohol Dehydrogenase (Liver).- 4. ?-Amylase (Ca++-activated).- 5. Comments on Non-Inhibition by Fluoride of some Enzymes Activated by Divalent Metals.- IV. Enzymes Inhibited by Fluoride; No Requirement for Metal Ions Demonstrated.- A. Liver Esterase.- B. 5'-Adenylic Acid Deaminase.- C. Phosphoglycerate Mutase.- D. Hydrazidase.- V. Enzymes, Inhibited by Fluoride, Containing Trivalent Metal Ions.- A. Catalase.- B. Peroxidase.- VI. Concluding Comments.- References.- 3: Changes in Cell Function Due to Inorganic Fluoride.- I. Introduction.- II. Effect of Fluoride on Metabolic Pathways.- A. Outline of Intermediary Metabolism.- B. Glycolysis.- C. Pyruvate Metabolism and Oxidation in the Tricarboxylic Acid Cycle.- D. Oxidative Phosphorylation.- E. Respiration.- F. Protein Synthesis.- G. The Response of Tissues to Hormones.- H. Fat Metabolism in Adipose Tissue.- I. Lipases.- III. Effects of Fluoride on Physical Activity of Cells.- A. Movement.- 1. Motility.- 2. Phagocytosis.- 3. Contractility.- B. Transport Across Cell Membranes.- 1. Intestinal Epithelium.- 2. Non-Polar Cells.- IV. Effects of Fluoride on the Growth and Development of Cells in Tissue Culture.- V. Concluding Remarks.- References.- 4: Pharmacology of Sodium Fluoride.- I. Introduction.- II. Effect of Sodium Fluoride on Blood Pressure and the Heart.- A. Hypotensive Activity of Fluoride.- B. Pressor Effect of Fluoride.- C. Stimulatory Effect of Sodium Fluoride on Isolated Heart Preparations.- III. Effect of Sodium Fluoride on the Gut.- A. Effect of Fluoride on the Gut, in Vivo.- B. Effect of Fluoride on Dog Gut, in Vitro.- IV. Effect of Sodium Fluoride on Respiration.- V. Summary and Conclusions.- References.- 5: Fluoroamino Acids and Microorganisms.- I. Introduction.- II. Fluoroamino Acids and Cellular Microorganisms.- A. General Toxicity and Effects on Growing Cells.- B. Incorporation of Fluoroamino Acids into Proteins.- C. Effects of Fluoroamino Acids on Specific Cell Functions.- 1. Cell Division.- 2. Motility.- 3. Capsule Formation.- 4. Regulation of Enzyme Synthesis and Activity.- 5. Transport Systems.- 6. Bacterial Sporogenesis.- 7. Respiration and Photosynthesis.- 8. Ribosome Synthesis.- 9. Antibiotic Production.- 10. Maintenance of Diploid State in Fungi.- 11. Virus and Bacteriocin Production.- D. Catabolism of Fluoroamino Acids by Bacteria.- E. Bacterial Adaptation to Fluoroamino Acids.- 1. Physiologic Adaptation.- 2. Amino Acid-Secreting Mutants.- 3. Mutants with Altered Transport Systems.- 4. Mutants with Altered Amino Acyl-tRNA Synthetases.- 5. Mutants with Altered Ribosomes.- References.- 6: Fluorine-Containing Steroids.- I. Introduction.- II. Fluoro Steroids with Respect to Glucogenic, Anti-Inflammatory and Mineralocorticoid Effect.- A. The 9?-Fluoro-Substitution in.- 1. Cortisol.- 2. ?1-Cortisol (Prednisolone).- 3. ?6-Cortisol.- 4. Other Pregnane Derivatives.- B. Fluorination at other Positions and in Combination with 9?-Fluoro.- 1. In Cortisone, Cortisol, Prednisone or Prednisolone.- a) 2?-Fluoro.- b) 4-Fluoro.- c) 6? -Fluoro and 6?,9? -Difluoro.- d) 15?-Fluoro and 9?,15?-Difluoro.- e) 16? -Fluoro, 9?,16?-Difluoro, 6?,16? -Difluoro and 6?,9?,16? -Trifluoro.- f) 16?-fluoro and 9?,16?-Difluoro.- 2. In other Pregnane Derivatives.- a) 1l?-Fluoro.- b) 12? -Fluoro.- c) 17? -Fluoro.- d) 21-Fluoro.- e) Fluorine in 16?,17? -Ketal.- C. Other Groups in.- 1. 9? -Fluorocortisol and 9?-Fluoroprednisolone.- a) 1-Hydroxy.- b) 2? -Methyl.- c) 4-Methyl and 4-Ethyl.- d) 6? - and 6?-Chloro.- e) 6? -Fluoromethyl.- f) 6? -Methoxy.- g) 6? -Methyl.- h) 7? -Acetylthio.- i) 16?-Acetoxy.- j) 16?-Chloro.- k) 16? -Ethyl.- 1) 16? -Fluoromethyl.- m) 16? -Hydroxy.- n) 116?,17?-Ketal.- o) 16? -Methoxy.- p) 16? - and 16?-Methyl.- q) 16-Methylene or ?15-16-Methyl.- r) 16?, 17?-Orthoesters (Cyclic).- s) 21-Methyl.- 2. Other 9?-Fluoropregnane Derivatives.- a) 6?-Methyl.- b) 16? -Chloro, Nitrogen and Sulfur Containing Groups.- e) 16? -Hydroxy and Acetonide.- d) 16? -Methyl.- e) 17?,21-Epoxy.- f) 21-Chloro, 16? -Hydroxy and Acetonide.- g) 21-Chloro, 16? -Hydroxy,2? -Methyl, Acetonide.- D. With More than one Change in the 9? -Fluorocortisol or 9? -Fluoroprednisolone Molecule.- 1. ?6, 16? -Hydroxy.- 2. 6?,7? -Dihydroxy.- 3. 6?,16? -Dimethyl.- 4. 6? -Fluoro, 16? -Hydroxy and Acetonide.- 5. 6? -Fluoro, 16? -Methyl.- 6. 6? -Fluoro, 21-Methyl.- 7. 6-Formyl, 3-Enol Ether, 16? -Hydroxy, Acetonide.- 8. 6? -Methyl, 16? -Hydroxy and Acetonide.- 9. ll?-Acetoxy, 16? -Hydroxy.- 10. 16? -Methyl, 17? -Methoxy.- 11. 17,20:20,21-Bismethylenedioxy.- 12. 20-Ketal Derivatives.- 13. 21-Sugar Derivatives, 16? -Hydroxy.- 14. 21-Tetrahydropyranyl Ether, 16? -Hydroxy, Acetonide.- E. Pyrazol Ring Attached to Ring A.- F. Other Groups in 6a-Fluoro Compounds without 9a-Fluoro Substitution.- 1. 6? -Fluoro, 2-Methyl, 16? -Hydroxy, Acetonide, ?1.- 2. 6? -Fluoro, 16? -Hydroxy, and 6? -Fluoro, 16? -Methyl.- 3. 6? -Fluoro, 16? -Hydroxy, ?8 and Acetonide.- 4. 6a-Fluoro, 3?-Acetoxy, 16? -Hydroxy Acetonide.- G. Analytical Problems in Studying Fluorosteroids.- 1. General Aspects.- 2. Extraction.- 3. Fluorosteroid Color Reaction.- 4. Determination in Urine as 17-Ketosteroids.- 5. Paper and Column Chromatography.- 6. Preparation of Tritium-Labeled Triamcinolone.- 7. Isomerization.- H. Metabolism.- 1. Absorption.- a) Intestinal.- b) Percutaneous.- c) Intra-Articular.- 2. In Vitro Studies.- a) Liver Slices or Homogenates.- b) Metabolism by Micro-Organisms.- c) Adrenal Metabolism of 9? -Fluoroandrostenedione.- 3. Plasma Protein Binding.- 4. In Vivo Studies.- a) Plasma Half-Life and Tissue Distribution.- b) Excretion of Metabolites.- I. Biological Effects of Fluorocorticoids.- 1. Microbiological Systems.- a) Growth Rate Stimulation.- b) Growth Rate Inhibition.- c) Enzyme Activity - Alkaline Phosphatase.- 2. Isolated Systems in Vitro.- a) Frog-Skin Sacs.- b) Frog Skin, Short Circuited.- c) Perfused Rabbit Heart.- d) Cat Papillary Muscle.- 3. Effects in Animals.- a) Liver Enzymes.- b) Thymus Enzymes.- c) Skin Enzymes.- d) Skin Composition.- e) Kidney. Infused Renal Artery.- f) Effects in Whole Animals.- g) Toxicology.- 4. Effects in Man.- a) Extrapolation from Animal Bioassays to Man.- b) Use of Corticosteroids.- c) Adrenal Suppression.- d) Side Effects of Therapeutic Doses.- e) Topical Effectiveness of Fluorosteroids.- III. Fluoro-Steroids with Respect to Gestagenic, Anti-Androgenic, Anti-Estrogenic, Anti-Ovulatory, and Anti-Gonadotrophic Effects.- A. The 9?-Fluoro-Substitution in.- 1. Progesterone and 11-Oxygenated Progesterone.- 2. 17? -Acetoxyprogesterone, 11-Oxygenated.- 3. ll?-Hydroxy-17?-Methyltestosterone.- B. Fluorination at other Positions.- 1. In Progesterone, and Its 9? -Halogenated and 11-Oxygenated Derivatives.- a) 2? -Fluoro.- b) 6? -Fluoro.- c) 6,6-Difluoro.- d) 11?-Fluoro.- e) 12? -Fluoro.- f) 17? -Fluoro.- g) 21-Fluoro.- h) 21,21-Difluoro.- i) 21,21,21-Trifluoro.- 2.In 17? -Acetoxyprogesterone.- a) 6? - and 6?-Fluoro, ?1 and ?6.- b) 21-Fluoro.- C. Other Groups in Combination with Fluorination in the Progesterone Molecule.- 1. 4-Fluoro, 6?, 16? -Dimethyl and 4,4-Difluoro Derivatives.- 2. 6? - and 6?-Fluoro, 16?,17? -Dihydroxy and Ketals.- 3. 6? -Fluoro, 16? -Methyl.- 4. 6? -Fluoro, 17? -Methyl, 6-Fluoro, 17? -Ethyl, ?6 and 6?, 21-Difluoro, 17? -Methyl.- 5. 6? -Trifmoromethyl, 17? -Acetoxy.- 6. 21-Fluoro, 6-Chloro, 17? -Aeetoxy, ?6.- 7. 21-Fluoro, 6a-Methyl, 17? -Acetoxy and ?6.- 8. 21-Fluoro, 6?, 16? -Dimethyl, 17? -Hydroxy and ?6.- 9. 21-Fluoro, 17? -Methyl, 6-Methyl and 6-Chloro, ?1 and ?6.- D. Fluorination in.- 1. Ethisterone, 19-Norethisterone and Derivatives thereof.- a) 5? -Fluoro, Dihydro, 19-Nor-10?-Hydroxy.- b) 6? -Fluoro.- c) 10?-Fluoro-19-Nor.- d) 16? -Fluoro, 17? - and 17?-Chloroethinyl.- 2. 9?,10? -Pregnanes - 6-Fluoro, ?6 and 17? -Acetoxy.- E. Miscellaneous.- F. Biological Effects of Fluoroprogestational Steroids.- 1. Anti-Estrogenic Action.- 2. Anti-Gonadotropin Activity.- 3. Anti-Ovulatory Activity.- IV.Fluoro-Steroids with Respect to Androgenic, Anabolic, Anti-Androgenic, Anti-Tumor and Anti-Gonadotropic Effect.- A. The 9? -Fluoro Substitution in.- 1. 11?-Hydroxy-?4-Androstene-3,17-Dione.- 2. 17? -Methyltestosterone, 11-Oxygenated.- B. Muorination at other Positions in ?4-Androstene-3-one or Dihydro Compounds.- 1. 2?- and 2?-Muoro.- 2. 4-Fluoro.- 3. 6?- and 6? Fluoro.- 4. 6,6-Difluoro.- 5. 16? - and 16?-Fluoro and 16,16-Difluoro.- C. Other Groups in ?4-Androstene-3-one or Dihydro Compounds in Combination with Fluorination.- 1. 9? -Fluoro, 11?-Hydroxy, 7? -Acetylthio.- 2. 9? -Fluoro, 11?-Hydroxy, 16? -Methyl.- 3. ll?-Fluoro, 9? -Halogen.- 4. 16? -Fluoro, 16?-Methyl.- D.Fluorination in other Androstane-3-one Derivatives.- 1.19-Nor-Derivatives.- a) 4,4-Difluoro.- b) 5? -Fluoro, 10?-Hydroxy.- c) 10? -Fluoro.- 2. 9?, 10?.- 6-Fluoro, ?4,6.- E. Fluorination in Androstane Compounds without 3-Keto.- 1. In the Ring.- a) 3?-Fluoro.- b) 9?-Fluoro, 11? -Hydroxy, 3-Methylene.- 2. In Side Chain.- a) 2-Fluoromethyl and 2-Difluoromethyl, ?2.- b) 2?, 3? - and 2?, 3?-Difluoromethylene.- F. Miscellaneous.- G. In Vitro Metabolism.- H. Biological Effects of Fluoro Androgenic-Anabolic Steroids.- 1. Growth Stimulation in Man.- 2. Anti-Androgenic Action.- V. Fluoro-Steroids with Respect to Estrogenic, Hypocholesterolemic, Anti-Gonadotropic and Anti-Tumor Effects.- A. Fluorination in.- 1. Ring-A Aromatic Steroids.- a) 3-Fluoro.- b)4-Fluoro.- c) 16? -Fluoro, 16?-Cyano.- d) 16,16-Difluoro.- 2. 19-Norethisterone.- 10?-Fluoro.- 3. In Side Chain.- 17?-(2-Fluoroethyl)Ether.- VI. Fluoro Steroids with Respect to Anti-Mineralocorticoid Effect.- VII. Anti-Cancer Effects of Fluoro Steroids.- VIII. Structure-Activity Relationships and Influence of Fluorination.- IX. Other Fluoro-Steroids.- References.- 7: Biological Properties of Selected Fluorine-Containing Organic Compounds.- I. Introduction.- A. Preparation of Biologically Active Compounds of Fluorine.- B. Mechanisms of Action of Organically Bound Fluorine.- II. The Carbon-Fluorine Bond.- A. Physical Properties.- B. In Vivo Synthesis of the C-F Bond.- III. Metabolism of Organic Fluoroeompounds.- A. In Vivo Rupture of the C-F Bond.- 1. Microbial Cleavage of the C-F Bond.- a) Aliphatic Compounds.- b) Aromatic Compounds.- 2. Mammalian Cleavage of the C-F Bond.- a) Aliphatic Compounds.- i) Fluoroacetic acid.- ii) Halogenated Anesthetics.- iii) Fluorine-Containing Sugars.- iv) Fluoro-Oxaloacetate.- b) Aromatic Compounds.- i) Fluoronitrobenzenes.- ii) 4-Fluorophenylalanine.- iii) Acetanilides and Anilines.- iv) 4'-Fluoro-4-dimethylaminoazobenzene.- 3. Cleavage of the C-F Bond in Plants.- B. Biotransformations not Involving the C-F Bond.- 1. Bacterial Metabolism.- a) Fluoronicotinic Acids.- b) Fluorobenzoic Acids.- c) p-Fluorophenylalanine.- d) 6-Fluorotryptophan.- e) 3-Deoxy-3-Fluoro-D-Glucose.- 2. Mammalian Metabolism.- a) Fluorobenzene.- b) Fluorobenzoic Acids and Amides.- c) Fluorothiobenzoic Acids.- d) Trifluralin.- e) Fluorine-Substituted Amino Acids.- i) m-Fluorotyrosine.- ii) Fluorophenylalanines.- iii) 5-Fluorotryptophan.- f)Other Compounds.- IV. Biological Effects of Organic Compounds of Fluorine.- A. Effects of Amino Acid Analogues on Protein Synthesis and Enzyme Induction in Mammalian Systems.- 1. Growth.- 2. Incorporation into Protein.- 3. Effects on Amino Acid Transport.- 4. Effects on Activating Enzyme.- 5. Metabolism of Fluorine-Containing Amino Acid Analogues.- B. Effects of Organic Fluoro Compounds Upon Microorganisms.- C. Organic Fluoro Compounds in Experimental Cancer Studies.- 1. Anticancer Agents.- 2. Production of Experimental Cancers.- a) Derivatives of Dimethylaminoazobenzene.- b) Fluorinated Derivatives of 2-Acetylaminofluorene and Related Compounds.- c) Fluorinated Derivatives of 10-Methyl-1,2-Benzanthracene.- d) Fluorotricycloquinazoline.- D. Psychosedative Drugs.- 1. Phenothiazines.- a) Structure - Activity Relationships.- b) Mode of Action.- i) Erythrocyte Membrane.- ii) Adrenomedullary Granules.- iii)ATPase.- iv) Miscellaneous.- c) Metabolic Fate.- d) Toxicity.- e) Analysis.- 2. Butyrophenones.- a) Structure - Activity Relationships.- b) Mode of Action.- c) Metabolic Fate.- i) Absorption, Distribution and Excretion.- ii) Biotransformations.- d) Toxicity.- E. Diuretic Agents.- 1. Benzothiadiazine Dioxides.- a) Structure - Activity Relationships.- b) Mode of Action.- c) Metabolic Fate.- i) Absorption, Distribution and Excretion.- ii) Biotransformation.- d) Toxicity.- e) Analysis.- 2. Other Diuretic Agents.- F. Compounds Affecting the Thyroid Gland.- 1. 3-Fluorotyrosine.- 2. 3-Fluoro-5-Iodotyrosine.- 3. 3,5-Difluorotyrosine.- 4. 3-Fluoro-4-Hydroxyphenylacetic Acid.- 5. 6-Trifluoromethylthiouracil.- 6. Compounds Related to Thyroxine.- G. Antihypertensive Agents.- 1, Diuretic Drugs.- a) Benzothiadiazines.- i) Nondiuretie Benzothiadiazines.- b) Phthalimidines.- 2. Catecholamine Depleting Agents.- a) Guanidine Derivatives.- H. Adrenergic Blocking Agents.- I. Pressor Amines.- J. Monoamine Oxidase Inhibitors.- 1. Derivatives of Hydrazine.- 2. Derivatives of Cyclopropylamine.- 3. Indole Derivatives.- 4. Miscellaneous.- K. Hypocholesteremic Agents.- 1. Hormones.- 2. Basic Carbinols and Related Compounds.- 3. Miscellaneous.- L. Hypoglycemic Agents.- 1. Sulfonylureas.- 2. Sulfamylureas.- 3. Triazines.- 4. Thiadiazoles and Oxidiazoles.- 5. Pyrazoles.- 6. Hydantoins.- M. Penicillins.- 1. Addition of Precursors to Fermentation Media.- 2. Modification of the Penicillin Nucleus.- 3. Total Synthesis.- 4. Resistance to Penicillinase.- N. Plant Growth Regulators.- References.- Author Index.