Contributions of paul ehrlich

Contribution of Paul Ehrlich in early chemotherapy and the development of parameters on which future drugs are developed.

1. “Founder of Chemotherapy” Paul Ehrlich Presented by: Dr. Pratibha Tiwari

2. Nobel Prize of Physiology and Medicine 1908 Founder of Modern Chemotherapy Contribution in the field of: Histology, Haematology, Immunology, Oncology, Microbiology and Pharmacology

3. Standardization of manufacturing of Anti-Diphtheria serum Discovery of Salvarsan ( arsphenamine ): First Magic Bullet Synthesis of anti- bacterials Concept of chemoreceptor and chemotherapy Concept of concept of linking chemical structure of compounds to their pharmacological activities Concept of developing resistance

4. Staining Procedures... He concluded that strong affinities must exist between biological structures and the stain applied. Studied entire spectrum of staining techniques and chemistry involved Differential staining of tissues using Methylene Blue First detect bilirubin in urine of the patients of Jaundice ( Diazo reaction) Stained and named “Mast cells” using alkaline dyes Differentiated Leukocytes into Basophils , Eosinophils and Neutrophils First showed nucleated RBCs and subdivided into Megaloblast , Microblast , Normoblast and Poikiloblast Methylene blue also stained the long appendages of nerve cells Developed a new staining procedure for Mycobacterium which later became basis of current Zielh-Neelsen Acid- fact staining

5. Serum research... Formulated “ Side-chain Theory ” proposing a possible explanation for the process of immunity. Gave concept of acquired immunity and mechanism of transfer of immunity from mother to foetus. Alongwith Emil Behring work on Standardization of Anti- Diptheria serum production process : “ Valency of serums ” Side-chain Theory Introduced the term “Receptor”, developed the theory of chemoreceptor. A side-chain from a given cell might have a molecular structure that allowed it to bind with a specific toxin or bacteria leading to its loss of action. This leads to trigger production of more such side-chains and secreted in the blood. This way small amount of toxin of toxin can produce a large amount of anti-toxin. Ehrlich later argued that certain chemoreceptors on parasites, microorganisms, and cancer cells would be different from analogous structures in host tissues, and that these differences could be exploited therapeutically

6. Chemotherapy: In vivo staining Methylene blue as anti-malarial agent Transition from Experimental pharmacology to Therapeutic pharmacology The search for a “ Chemotherapia specifica ” : concept of Structure–Activity Relationship Development of first synthetic chemotherapeutic agent: From Atoxyl to Salvarsan and Neosalvarsan against syphilis Cancer research: Achieved insight that when tumors are cultivated by transplanting tumor cells, their malignancy increases from generation. If primary tumor is removed, then metastasis precipitously increases.

7. Paul Ehrlich’s Magic Bullets:   If a compound could be made that selectively targeted a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity . Need to study the relationship between the chemical composition of drugs and their mode of action in the organisms Selective drugs were needed which, like anti-toxins aimed specifically at their corresponding toxins High parasitotropism with low organotropism

8. Development of Arsenicals

9. In 1858, David Livingston suggested use of 1% aqueous solution of potassium arsenite (Fowler’s reagent) for the treatment of sleeping sickness 1859- first synthesised ‘ Atoxyl ’ ( Aminophenyl arsenic acid) by Pierre Jaceus Antoine Be’champ Paul Ehrlich and Alfred Bertheim first derived structure of Atoxyl Atoxyl : high doses for prolonged period were required(2% patients get optic nerve atrophy) in use till 1905. Acetylatoxyl ( arsacetin ): less toxic but high doses needed ; damage to vestibular nerve Arsenoxides and Arsenobenzenes (reduced products; metabolites) Arsenophenyl glycine : effective against sleeping sickness, low toxicity,also effective against spirochetes or syphillis ; 1907 Arsenophenol

10. Arsphenamine or Salvarsan (Ehrlich and Hata ; 1909 against syphillis ):30% arsenic, treatment 18 months long with 20 arsphenamine injestions and 30-40 bismuth injections; difficult to prepare on large scale Neoarsphenamine or neosalvarsan : sodium bisulphite aldehyde derivative; 19 % arsenic, less toxic , short treatment time, easily oxidised In 1930 Mapharsen ( oxophenarsine , metabolite of arsphenamine ) very stable. Melarsobol or Arsobal , injectable arsenic derivative remains in use as the treatment of choice for sleeping sickness.

11. Atoxyl ( arsernic acid anilide ) Atoxyl ( Aminophenyl arsenic acid) Acetylatoxyl Arsacetin Spirasyl ( arsenophenylglycine ) Arsenopheno l Arsphenamine ( diaminodioxyarsenobenzol ) Salvarsan Neoarsphenamine Neosalvarsan Oxophenarsine Mapharsen Melarsoprol Arsobal Trimers and Pentamers Of arsphenamine ( Salvarsan main constituents)

12. Development of Sufanilamides

13. Sulfa drugs or Sulfanilamides First synthetic chemotherapeutic agent effective against bacterial disease . Gerhard Domagk( 1932 )  hypothesized that since the dye worked by binding to the proteins in fabric and leather, it might also bind to the proteins in bacteria , thus inhibiting their action In 1936, Prontosil or sulfamidochrysoidine , a dye,   was successfully used against puerperal sepsis, also  effective against meningitis  , pneumonia, and streptococcal infections, childbed fever , blood poisoning, gonorrhea , burns from gas warfare, and other serious burns Most effective sulfa drugs were sulfapyridine for pneumonia, sulfathiazole against pneumonia and staphylococcus, sulfaguanadine to treat  dysentery , and sulfadiazine , which worked against pneumonia, strep and staph. Prontosil

14. Prontosil

15. SAR of sulphanilamides