PHAR1101 Lecture Notes - Lecture 9: Arsphenamine, Prontosil, Penicillium
Penicillin:
Beginning of the antibiotic era:
2 innovative drugs found via animal testing of compound libraries:
- Salvarsan: - 1911 - syphilis treatment
- Prontosil: 11935 – streptococcal infections
How sulfonamides paved the way:
- Proved that fatal infectious diseases ere aageale ith drugs (i.e.
pneumonia)
- Fostered hospital microbiology infrastructure
- well equipped labs
- handling lots of patient samples
- sample analysis protocols
- dosing guidelines
- trained medical, nursing and scientific staff.
Limitations of salarsa ad sulfa drugs:
- Narrow spectrum of action – didt kill rage of ateria speies
- Toxicity to patient (salvarsan had arsenic)
- Skin stained by prontosil
- Bacterial resistance a major problem with sulfa drugs
The penicillin mold – an untapped goldmine for drugs:
1870 – Burdon-sanderson, UK, attracted by Pasteur’s germ theory.
1871 – reports of penicillium mold (from fruit and jam) to stop bacterial growth
Joseph Lister (1827-1912) found antiseptic properties of phenol.
- Observed curative properties of penicillium soaked dressings on infected wounds.
Alexander Fleming:
1881 born in Scotland
Watched soldiers die of infected wounds in medical corps of WW1
- Noted failure of antiseptics to cure internal infections
1928, director of inoculation lab in London
Worked on anti-bacterial properties of human nasal secretions – lysozyme
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Fluke observation:
July 1928 – took 2 week vacay.
Left used agar plates (streptococcal cultures) on lab bench.
- Unusual cold snap (growth advantage to penicillium mold contaminant)
- Returned to work and noticed inhibitory effect of mold on bacterial growth.
Made bright yellow filtered broth from penicillium notatum mold.
- Very active against growing Staph cultures as well as other bacterial species.
- Non irritating if applied to tissue directly
- Safe if injected into healthy mice (non-staph infected)
- Couldt purify atie heial (penicillin unstable)
Forgot about drug for 13 years.
Howard Florey:
University of Adelaide-trained pathologist.
Professor of pathology at Oxford.
1937 – hired Ernst Chain biochemist)
- chain overcame penicillin instability and extraction problems
- prepared penicillin as stable lyophilized salt at pH 5-8.
Success in first animal tests:
- staph infected mice with treatment mostly made full recovery
- no treatment mice died in 2-3 days.
First human tests:
Forty three y.o policeman with invasive Strep and Staph infections
- 200mg penicillin (i.v. drip) + 100mg every 3 hours.
- 24 hour, strong recovery but drug ran out after 3 days
- Administered recycled penicillin (from urine)
- good response but death after drug ran out
Subsequent patient also died (girl) before success with 2 patients.
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
2 innovative drugs found via animal testing of compound libraries: Proved that fatal infectious diseases (cid:449)ere (cid:858)(cid:373)a(cid:374)agea(cid:271)le(cid:859) (cid:449)ith drugs (i. e. pneumonia) Narrow spectrum of action did(cid:374)(cid:859)t kill ra(cid:374)ge of (cid:271)a(cid:272)teria spe(cid:272)ies. Bacterial resistance a major problem with sulfa drugs. The penicillin mold an untapped goldmine for drugs: 1870 burdon-sanderson, uk, attracted by pasteur"s germ theory. 1871 reports of penicillium mold (from fruit and jam) to stop bacterial growth. Joseph lister (1827-1912) found antiseptic properties of phenol. Observed curative properties of penicillium soaked dressings on infected wounds. Watched soldiers die of infected wounds in medical corps of ww1. Noted failure of antiseptics to cure internal infections. Worked on anti-bacterial properties of human nasal secretions lysozyme. Left used agar plates (streptococcal cultures) on lab bench. Unusual cold snap (growth advantage to penicillium mold contaminant) Returned to work and noticed inhibitory effect of mold on bacterial growth. Made bright yellow filtered broth from penicillium notatum mold.
