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Birth of Chemotherapy

Dreams of a “Magic Bullet”. Birth of Chemotherapy. Presentation Outline. History Salvorsan Sulfa Penicillin “Sulfas” Antimetabolites antibiotic synergism Ideal properties Sources. Filename: Chemotheraphy.ppt. Semmelweiss. Jena, Austria “Laying in” hospitals Peurperal fever

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Birth of Chemotherapy

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  1. Dreams of a “Magic Bullet” Birth of Chemotherapy

  2. Presentation Outline • History • Salvorsan • Sulfa • Penicillin • “Sulfas” • Antimetabolites • antibiotic synergism • Ideal properties • Sources Filename: Chemotheraphy.ppt

  3. Semmelweiss • Jena, Austria • “Laying in” hospitals • Peurperal fever • Cleanliness in surgery

  4. Joseph Lister Developed antiseptic surgery

  5. Early Antibiotics • Salvarsan 606- failure • Prontosil- developed by careful research • Penicillin- discovered accidently

  6. Paul Ehrlich • Noble Prize • Chemotherapy • Theory of immunity

  7. Salvarsan 606 • Paul Ehrlich • early 1900’s • syphilis • arsenic + organic compound • Aniline dyes - • wasn't able to find the "magic bullet”

  8. Prontosil • 1930's, Gerhard Domagk • Prontosil • 1935, Jacques and Therese Trefoncel • discovered that the active compound in Prontosil was Sulfanilamide • sulfanilamide “ Sulfas”

  9. Sulfa Drugs

  10. NH2SO2 NH2 Sulfanilamide NH2 HOOC PABA Sulfa vs PABA

  11. Effectiveness of Sulfas • Organism must synthesis folic acid • eg E coli • no effect if folic acid is required • eg man and many microbes • BACTERIOSTATIC

  12. Sulfisoxazole Sulfanilamide Prontosil Structure of Sulfa Drugs

  13. Pteridine synthetase [GTP] Dihydropteroic acid Dihydrofolate Synthetase L- Glutamine Dihydrofolic Acid 2 NADPH Dihydrofolate synthetase 2 NADP+ Tetrahydrofolic Acid Thymidine Purines Methionine DNA DNA, RNA tRNa, Proteins Folic Acid Metabolism PABA + pteridine Sulfonamide Trimethoprim

  14. Sulfonamide Trimethoprim Thymidine Purines Methionine DNA DNA, RNA tRNa, Proteins Folic Acid Inhibition PABA + pteridine Dihydropteroic acid Dihydrofolic Acid Tetrahydrofolic Acid

  15. Sulfisoxazole Trimethoprim Antibiotic Synergism

  16. Antibiotic Synergism • Sulfonamide + trimethoprim • Effective dosage 10% of two separately • Broader spectrum of action • Reduce emergence of resistant strains

  17. Alexander Flemming • Discovered penicillin

  18. Penicillin • 1928, Alexander Fleming • antibacterial activity in Penicillium mold (called it Penicillin) • 1938, Howard Florey and Ernst Chain • developed Penicillin as an effective antibiotic

  19. Inhibition Inhibition of Staphylococcus by Penicillium Staphylococcus Colony Penicillium mould

  20. Penicillin prevents Assembly of Bacterial Cell Walls

  21. Penicillium Growing in Broth

  22. Mass Production Used Many Flasks

  23. Penicillium in Vats

  24. Antimicrobial Therapy • Antimicrobics • substances produced by microbes that inhibit other microbes • Semi-synthetic antibiotics • naturally produced but altered • Synthetic antibiotics: • derived from chemicals

  25. Ideal Properties of an Antibiotic • Low toxicity for patient • kills the invading microorganism without damaging the host • no adverse side reactions • non allergenic • High toxicity for microbe • bactericidal not bacteriostatic • broad spectrum • Low risk of other infections

  26. More Characteristics • drug can be administered orally or parenterally (by injection) • Soluble in tissue fluids • absorbed by and dissolved in tissues or body fluids • levels of active drug sustained long enough to kill the invading agent • Long “Shelf” life

  27. Still More Characteristics • Low probability of resistance • Microbial drug resistance develops slowly • microbicidal rather than microbistatic • Not inactivated by organic material • Assists the host in eliminating the infecting microbe • Not a powerful allergen

  28. Sources of Antibiotics Most spore-forming microorganisms • Fungi • Penicillium penicillin, • Cephalosporium griseofulvin • Bacteria • Bacillusbacitracin, polymyxin, tyrothricin, colimycin, gramicidin • StreptomycetesAminoglycosides, chloramphenicol, erythromycin, tetracylcine, nystatin...

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