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a b c Lalchhandama, K. (2020). "Reappraising Fleming's Snot and Mould". Science Vision. 20 (1): 29–42. doi: 10.33493/scivis.20.01.03. ISSN 0975-6175.
de Scoville, C.; Brouwer, C. De; Dujardin, M. (1999). "Nobel chronicle: Fleming and Gratia". The Lancet. 354 (9, 174): 258. doi: 10.1016/S0140-6736(05)66334-9. ISSN 0140-6736. PMID 10421340. S2CID 11659394.
International Code of Botanical Nomenclature (VIENNA CODE). Appendix IV: Nomina specifica conservanda et rejicienda. B. Fungi". International Association of Plant Taxonomy. 2006 . Retrieved 17 June 2020. Mathews, John A. (2008). "The Birth of the Biotechnology Era: Penicillin in Australia, 1943–80". Prometheus. 26 (4): 317–333. doi: 10.1080/08109020802459306. ISSN 0810-9028. S2CID 143123783. Arseculeratne, S. N.; Arseculeratne, G. (May 2017). "A re-appraisal of the conventional history of antibiosis and Penicillin". Mycoses. 60 (5): 343–347. doi: 10.1111/myc.12599. PMID 28144986. S2CID 21424547. US 2442141,Moyer, A. J.,"Method for Production of Penicillin",issued 25 March 1948, assigned to US Agriculture ; US 2443989,Moyer, A.J.,"Method for Production of Penicillin",issued 22 June 1948, assigned to US Agriculture ; US 2476107,Moyer, A. J.,"Method for Production of Penicillin",issued 12 July 1949, assigned to US Agriculture
Nicolaou, K.C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. (January 2000). "The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century". Angewandte Chemie. 39 (1): 44–122. doi: 10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L. ISSN 1433-7851. PMID 10649349. There were rumours that the committee would award the prize to Fleming alone, or half to Fleming and one-quarter each to Florey and Chain. Fulton and Dale lobbied for the award to be given to Florey. [201] The Nobel Assembly at the Karolinska Institute did consider awarding half to Fleming and one-quarter each to Florey and Chain, but in the end decided to divide it equally three ways. [199] On 25 October 1945, it announced that Fleming, Florey and Chain equally shared the 1945 Nobel Prize in Physiology or Medicine "for the discovery of penicillin and its curative effect in various infectious diseases." [202] [203] When The New York Times announced that "Fleming and Two Co-Workers" had won the prize, Fulton demanded – and received – a correction in an editorial the next day. [204] [205] [206] In addition to increased production at the Dunn School, commercial production from a pilot plant established by Imperial Chemical Industries became available in January 1942, and Kembel, Bishop and Company delivered its first batch of 910 litres (200impgal) on 11 September. Florey decided that the time was ripe to conduct a second series of clinical trials. Ethel Florey was placed in charge, but while Howard Florey was a consulting pathologist at Oxford hospitals, and therefore entitled to use their wards and services, Ethel, to his annoyance, was accredited merely as his assistant. Doctors tended to refer patients to the trial who were in desperate circumstances rather than the most suitable, but when penicillin did succeed, confidence in its efficacy rose. [97] The next stage of the process was to extract the penicillin. The liquid was filtered through parachute silk to remove the mycelium, spores and other solid debris. [66] The pH was lowered by the addition of phosphoric acid and the resulting liquid was cooled. [67] Chain determined that penicillin was stable only with a pH of between 5 and 8, but the process required one lower than that. By keeping the mixture at 0°C, he could retard the breakdown process. [68] In this form the penicillin could be drawn off by a solvent. Initially ether was used, as it was the only solvent known to dissolve penicillin, but it is highly inflammable and toxic. At Chain's suggestion, they tried using the much less flammable amyl acetate instead, and found that it also worked. [66] [69] [70] [71] Ernst Chain in his laboratorya b c Neushul, P. (1993). "Science, Government, and the Mass Production of Penicillin". Journal of the History of Medicine and Allied Sciences. 48 (4): 371–395. doi: 10.1093/jhmas/48.4.371. ISSN 0022-5045. PMID 8283024. a b c Abraham, E. P.; Chain, E.; Fletcher, C. M.; Florey, H. W.; Gardner, A. D.; Heatley, N. G.; Jennings, M. A. (16 August 1941). "Further Observations on Penicillin". The Lancet. 238 (6, 155): 177–189. doi: 10.1016/S0140-6736(00)72122-2. ISSN 0031-6970. PMID 1541313. Efforts were made to coax the mould into producing more penicillin. Heatley tried adding various substances to the medium, including sugars, salts, malts, alcohol and even marmite, without success. [63] At the suggestion of Paul Fildes, he tried adding brewing yeast. This did not improve the yield either, but it did cut the incubation time by a third. [59] The team also discovered that if the penicillin-bearing fluid was removed and replaced by fresh fluid, a second batch of penicillin could be prepared, [59] but this practice was discontinued after eighteen months due to the danger of contamination. The mould had to be grown under sterile conditions. [64] Abraham and Chain discovered that some airborne bacteria produced penicillinase, an enzyme that destroys penicillin. [65] It was not known why the mould produced penicillin, as the bacteria penicillin kills are no threat to the mould; it was conjectured that it was a byproduct of metabolic processes for other purposes. [64] a b Wainwright, M. (February 1993). "The mystery of the plate: Fleming's discovery and contribution to the early development of penicillin". Journal of Medical Biography. 1 (1): 59–65. doi: 10.1177/096777209300100113. ISSN 0967-7720. PMID 11639213. S2CID 7578843.
I have been frequently asked why I invented the name "Penicillin". I simply followed perfectly orthodox lines and coined a word which explained that the substance penicillin was derived from a plant of the genus Penicillium just as many years ago the word " Digitalin" was invented for a substance derived from the plant Digitalis. [29] St Mary's Hospital showing Fleming's lab and Praed Street Florey, M.E. (27 March 1943). "General and Local Administration of Penicillin". The Lancet. 241 (6239): 387–397. doi: 10.1016/S0140-6736(00)41962-8. ISSN 0140-6736. Serie Forschung und Industrie: Sandoz". Medical Tribune (in German) (45/2005) . Retrieved 2 August 2009. On 12 February, Fletcher administered 200mg of penicillin, following by 100mg doses every three hours. Within a day of being given penicillin, Alexander started to recover; his temperature dropped and discharge from his suppurating wounds declined. By 17 February, his right eye had become normal. However, the researchers did not have enough penicillin to help him to a full recovery. Penicillin was recovered from his urine, but it was not enough. In early March he relapsed, and he died on 15 March. Because of this experience and the difficulty in producing penicillin, Florey changed the focus to treating children, who could be treated with smaller quantities of penicillin. [94] [95]Heatley developed a penicillin assay using agar nutrient plates in which bacteria were seeded. Short glass cylinders containing the penicillin-bearing fluid to be tested were then placed on them and incubated for 12 to 16 hours at 37°C. By then the fluid would have disappeared and the cylinder surrounded by a bacteria-free ring. The diameter of the ring indicated the strength of the penicillin. [67] An Oxford unit was defined as the purity required to produce a 25mm bacteria-free ring. [57] It was an arbitrary measurement, as the chemistry was not yet known; the first research was conducted with solutions containing four or five Oxford units per milligram. Later, when highly pure penicillin became available, it was found to have 2,000 Oxford units per milligram. [72] Yet in testing the impure substance, they found it effective against bacteria even at concentrations of one part per million. Penicillin was at least twenty times as active as the most powerful sulfonamide. [68] The Oxford unit turned out to be very small; treating a single case required about a million units. [73] Hodgkin, D. C. (July 1949). "The X-ray analysis of the structure of penicillin". Advancement of Science. 6 (22): 85–89. ISSN 0036-8075. PMID 18134678. The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active penicillin V, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin. Ampicillin was developed by the Beecham Research Laboratories in London. When introduced to clinical use in 1961 it was the first semisynthetic penicillin that could be taken orally that was effective against both Gram-negative and Gram-positive organisms. [208] It was more advantageous than the original penicillin as it offered a broader spectrum of activity against both Gram-positive and Gram-negative bacteria, whereas the original was only effective against Gram-positive. [208] Amoxicillin In Kundl, Tyrol, Austria, in 1952, Hans Margreiter and Ernst Brandl of Biochemie developed the first acid-stable penicillin for oral administration, penicillin V. [171] American chemist John C. Sheehan at the Massachusetts Institute of Technology (MIT) completed the first chemical synthesis of penicillin in 1957. [172] [173] [174] Sheehan had started his studies into penicillin synthesis in 1948, and during these investigations developed new methods for the synthesis of peptides, as well as new protecting groups—groups that mask the reactivity of certain functional groups. [174] [175] Although the initial synthesis developed by Sheehan was not appropriate for mass production of penicillins, one of the intermediate compounds in Sheehan's synthesis was 6-aminopenicillanic acid (6-APA), the nucleus of penicillin. [176] [177]
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