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Chemotherapy by Paul ehrlich
The document discusses the development of chemotherapy, spearheaded by Paul Ehrlich, who introduced the concept of targeting specific pathogens with chemical agents rather than using broad-spectrum treatments. It details Ehrlich's biography, major discoveries such as the diphtheria antitoxin and salvarsan for syphilis, and the evolution of antimicrobial drugs including antibiotics and their mechanisms of action. Furthermore, it highlights the challenges of antimicrobial resistance and outlines the importance of selective toxicity in modern chemotherapy applications.
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Chemotherapy by Paul ehrlich
- 1. PAUL EHRLICH DEVELOPEDMODERN CONCEPT OF CHEMOTHERAPY AND CHEMOTHERAPEUTIC AGENTS Presented by Naraino Majie Nabiilah & Joorawon Svenia Date: 21st October2014
- 2. Table of Contents • Introduction • Biography of Paul Ehrlich • Development of chemotherapy • Antimicrobial chemotherapy • General characteristics of antimicrobial drugs • Determination of antimicrobial drug activity • Chemotherapeutic agents and their mechanism of action • Factors influencing the effectiveness of antimicrobial drugs • Antimicrobial resistance • Conclusion
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- 4. INTRODUCTION • Chemotherapyis the treatment of disease through customized chemical compounds which have specific biological targets and do not attack the entire organism which contains the target. • Dr. Paul Ehrlich was the first person to treat disease using chemicals. • Before him medical treatments were broad spectrum. • He fathered the idea that a medical treatment could be custom made to target the specific cause of disease.
- 5. INTRODUCTION • PaulEhrlich had been searching for chemicals that could kill infectious microbes without harming their human hosts. • Chemotherapeutic agents (CA) are chemical agents that are used to treat disease. • Antibiotics are microbial products or their derivatives that kill or inhibit susceptible microorganisms
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- 7. BIOGRAPHY • BornMarch 14, 1854 • He was a microbe hunter • Cartooned as Doctor Phantasus • Known as the father of chemotherapy • Ehrlich defined chemotherapy as the use of chemical substances, especially those produced synthetically, to destroy pathogenic microorganisms within the body. • He was a revolutionist-interested in Histological stain
- 8. BIOGRAPHY • Hestudies how WBC would stain. • This led to the discovery of methyl violet used to stain G+ bacteria and safranin for G-bacteria. • In 1878, he had his own laboratory where he developed method of staining tubercule bacillus. • He was infected with tuberculosis in 1887, went to Egypt and recovered after treatment.
- 9. BIOGRAPHY • Cameback and attempted to find a cure for diphtheria. • In 1892, diphtheria antitoxin successfully produced. • Awarded Nobel prize for this discovery. • Wanted to produce a magic substance which will target the desired site only. • Birth of Antimicrobial chemotherapy. – Tryptan red aka arsenophenol glycine and arsenic containing compounds were found to be effective against trypanosomes.
- 10. BIOGRAPHY • In1907, Salvarsan was used against trypanosomes but was uneffective. • Salvarsan was found to be effective against syphilis and this remained the most effective drug until discovery of penicillin by Fleming. • Chemotherapy research went on while Ehrlich health was declining. • Died in August 1915 at the age of 61. • Now, the concept of Ehrlich chemotherapy is being employed in modern chemotherapy.
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- 12. DEVELOPMENT OF CHEMOTHERAPY • Paul Ehrlich (1904–1909)—aniline dyes and arsenic compounds • Gerhard Domagk, and Jacques and Therese Trefouel (1939)—sulfanilamide • Ernest Duchesne (1896) discovered penicillin, however, this discovery was not followed up • Alexander Fleming (1928) accidentally discovered the antimicrobial activity of penicillin on a contaminated plate; however, follow-up studies did not show the drug would remain active in the body long enough to be effective
- 13. DEVELOPMENT OF CHEMOTHERAPY • Howard Florey and Ernst Chain (1939) aided by the biochemist, Norman Heatley, worked from Fleming’s published observations, obtained a culture from him, and demonstrated the effectiveness of penicillin • Selman Waksman (1944)—streptomycin; this success led to a worldwide search for additional antibiotics, and the field has progressed rapidly since then
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- 15. ANTIMICROBIAL CHEMOTHERAPY •The foundation of the 20th century chemotherapy was built on a search of antiprotozoal agents to be used against malaria and African sleeping sickness (trypanosomiasis). • The chemotherapeutic agents interfere directly with the multiplication of organisms and in concentrations not harmful to the host.
- 16. ANTIMICROBIAL CHEMOTHERAPY •Paul Ehrlich formulated the principles of selective toxicity and recognized the specific chemical relationship between parasites and drugs. • He introduced arsphenamine, an organic Selective toxicity is the ability to kill or inhibit microbial pathogen with minimal side effects to the host compound of arsenic, as a cure for syphillis and other spirochetal diseases. • Likewise, the organic arsenicals, and synthetic dyes, like trypan blue, were also found useful in the treatment of trypanosomiasis.
- 17. GENERAL CHARACTERISTICS OF ANTIMICROBIAL DRUGS
- 18. GENERAL CHARACTERISTICS OF ANTIMICROBIAL DRUGS • Selective toxicity—ability to kill or inhibit microbial pathogen with minimal side effects in the host – Therapeutic dose—the drug level required for clinical treatment of a particular infection – Toxic dose—the drug level at which the agent becomes too toxic for the host (produces undesirable side effects) – Therapeutic index—the ratio of toxic dose to therapeutic dose: the larger the better
- 19. GENERAL CHARACTERISTICS OF ANTIMICROBIAL DRUGS • Chemotherapeutic agents can occur naturally, be synthetic, or semisynthetic (chemical modifications of naturally occurring antibiotics) • Drugs with narrow-spectrum activity are effective against a limited variety of pathogens; • Drugs with broad-spectrum activity are effective against a wide variety of pathogens
- 20. GENERAL CHARACTERISTICS OF ANTIMICROBIAL DRUGS • Drug can be cidal (able to kill) or static (able to reversibly inhibit growth) • Minimal inhibitory concentration (MIC) is the lowest concentration of the drug that prevents growth of a pathogen; • Minimal lethal concentration (MLC) is the lowest drug concentration that kills the pathogen
- 21. DETERMINING THE LEVELOF ANTIMICROBIAL ACTIVITY
- 22. DETERMINING THE LEVELOF ANTIMICROBIAL ACTIVITY • Dilution susceptibility tests— – a set of broth-containing tubes are prepared; – each tube in the set has a specific antibiotic concentration; – to each is added a standard number of test organisms – The lowest concentration of the antibiotic resulting in no microbial growth is the MIC – Tubes showing no growth implies the lowest concentration of the drug from which the organism does not recover; this is the MLC
- 23. DETERMINING THE LEVELOF ANTIMICROBIAL ACTIVITY • Disk diffusion tests – Disks impregnated with specific drugs are placed on agar plates inoculated with the test organism; – clear zones (no growth) will be observed if the organism is sensitive to the drug; – the size of the clear zone is used to determine the relative sensitivity; – zone width also is a function of initial concentration, solubility, and diffusion rate of the antibiotic
- 24. DETERMINING THE LEVELOF ANTIMICROBIAL ACTIVITY • The Etest® – Especially useful for testing anaerobic microorganisms – Makes use of special plastic strips that contain a concentration gradient of an antibiotic; – Each strip is labeled with a scale of MIC values; – After incubation an elliptical zone of inhibition is observed and its intersection with the strip is used to determine the MIC
- 25. CHEMOTHERAPEUTIC AGENTS ANDTHEIR MECHANISM OF ACTION
- 26. Antibacterial Drugs 1.Inhibitors of cell wall synthesis are effective and selective because bacterial cell walls have unique structures not found in eukaryotic cells – Penicillin – Cephalosporins – Vancomycin and teicoplanine
- 27. Antibacterial Drugs 2.Protein synthesis inhibitors exploit the differences between prokaryotic and eukaryotic ribosomes – Aminoglycosides – Tetracyclines – Macrolides – Chloramphenicol
- 28. Antibacterial Drugs 3.Metabolic antagonists are structural analogs of metabolic intermediates that act as antimetabolites, inhibiting metabolic pathways; bacteriostatic – Sulfonamides or sulfa drugs • inhibit folic acid synthesis in bacteria (humans don’t synthesize folic acid, so are not affected); • resistance is increasing and many patients are allergic to these drugs; • includes p-aminobenzoic acid (PABA) – Trimethoprim • synthetic antibiotic that blocks folic acid production; • broad spectrum often combined with sulfa drugs
- 29. Antibacterial Drugs 4.Nucleic acid synthesis inhibitors block enzymes of transcription and translation; generally not as selectively toxic – Quinolones • synthetic drugs that inhibit bacterial DNA gyrase or topoisomerase II, thereby disrupting replication, repair, and other processes involving DNA; • broad spectrum; • includes nalidixic acid and ciprofloxacin (Cipro)
- 30. Antifungal Drugs •Fungal infections are more difficult to treat than bacterial infections because – the greater similarity of fungi and host limits the ability of a drug to have a selective point of attack; – furthermore, many fungi have detoxification systems that inactivate drugs • Superficial mycoses are infections of superficial tissues and can often be treated by topical application of antifungal drugs such as miconazole, nystatin, and griseofulvin, thereby minimizing systemic side effects
- 31. Antifungal Drugs •Systemic mycoses are more difficult to treat and can be fatal; – amphotericin B and flucytosine have been used with limited success because of its toxicity; • Subcutaneous mycoses (e.g., mycetomas) are treated with a mixture of therapies
- 32. Antiviral Drugs •Selectivity is a problem because viruses use the metabolic machinery of the host • Antiviral drugs target specific steps of life cycle, including viral uncoating and DNA replication (e.g., amantadine, vidarabine, acyclovir, cidofovir, and azidothymidine) • Anti-HIV drugs (e.g., AZT, ddI, 3TC) have four targets: – nucleoside reverse transcriptase inhibitors (NRTIs), – nonnucleoside reverse transcriptase inhibitors (NNRTIs), – protease inhibitors (block viral polypeptide processing), and – fusion inhibitors (block viral entry into cell); combinations of drugs often used • Tamiflu is a neuraminidase inhibitor that is used to treat influenza
- 33. Antiprotozoan drugs •Mechanisms of action for antiprotozoan drugs are largely unknown; as protozoans and humans are both eukaryotes, selective toxicity is difficult to achieve
- 34. FACTORS INFLUENCING THE EFFECTIVENESS OF ANTIMICROBIAL DRUGS
- 35. FACTORS INFLUENCING THEEFFECTIVENESS OF ANTIMICROBIAL DRUGS • Drug’s ability to reach the site of infection— this is greatly influenced by – the mode of administration (e.g., oral, topical, parenteral), – by exclusion from the site of infections (e.g., blood clots or necrotic tissue protects bacterium) • Susceptibility of pathogen—influenced by growth rate and by inherent properties (e.g., whether or not pathogen has target of the drug)
- 36. FACTORS INFLUENCING THEEFFECTIVENESS OF ANTIMICROBIAL DRUGS • Factors influencing drug concentration in the body – must exceed the pathogen’s MIC for the drug to be effective; – this will depend on the amount of drug administered, the route of administration, the speed of uptake, and the rate of clearance (elimination) from the body • Drug resistance has become an increasing problem
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- 38. DRUG RESISTANCE •Bacteria have evolved many strategies for resisting the action of antibiotics and antibacterial agents. • Bacteria that produce antibiotics do so to gain a selective advantage over other competing microbes in their natural environment. • If they were sensitive to their own metabolic products, such a selective advantage would be lost. • The problem of antibiotic resistance is becoming increasingly as more and more strains of pathogenic microorganisms are untreatable with commonly used antimicrobial agents.
- 39. DRUG RESISTANCE •Mechanisms of drug resistance – Prevent entrance of drug (e.g., alter drug transport into cell) – Pump the drug out of the cell once it has entered (efflux pump) – Enzymatic inactivation of the drug – Alteration of target enzyme or organelle – Use of alternative pathways and increased production of the target metabolite.
- 40. DRUG RESISTANCE •Overcoming drug resistance – Several strategies can be used to discourage emergence of drug resistance • administration of high doses, • simultaneous treatment with more than one drug, • limited use of broad-spectrum antibiotics – Development of new drugs and exploration of new treatment methods (e.g., phage treatment of bacterial infections).
- 42. CONCLUSION • Fromthe basic research of Dr Ehrlich, modern chemotherapy was developed. • Many drugs are now being produced to counteract the pathogens of many diseases. • Modern chemotherapy is also being employed in cancer treatment using the concept of selective toxicity. • Chemotherapeutic agents against infection should be used appropriately to prevent resistance.
- 43. REFERENCES • AntimicrobialChemotherapy By Roger Finch, Peter Davey, Mark H. Wilcox, William Irving • Chapter 11. ANTIBIOTICS AND CHEMOTHERAPEUTIC AGENTS BY I.H.Siddique http://compepid.tuskegee.edu/syllabi/pathobiology/microbiology/mic ro201/chapter11.html • Anon. General Characteristics of Antimicrobial. http://dev6.mhhe.com/textflowdev/genhtml/0073375268/P8.34.2.htm • Anon. Antimicrobial drugs. http://classes.midlandstech.edu/carterp/Courses/bio225/chap20/lectur e1.htm • Talaro KP and Chess B. Foundations in Microbiology. Principle of Antimicrobial Therapy. https://www.inkling.com/read/foundations-in-microbiology- talaro-chess-8th/chapter-12/principles-of-antimicrobial • Todar K. Antibiotics. http://lecturer.ukdw.ac.id/dhira/ControlGrowth/antibiotic.html
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