23 August, 2008

First clinical trials of penicillin in human

Dr. Florey said -----
We all know that when we compose a paper setting out -----
-------- discoveries we write it in such a way that the planning and unfolding of the
experiments appear to be a beautiful and logical sequence, but we all know that
the facts are that we usually blunder from one lot of dubious observations to another
and only at the end do we see how should have set about our problems.

Here, show the original description of first patient who received with penicillin therapy.
In the course of therapy, patient's urine were collected and re-extracted the penicillin.
The first patient died due to the shortage of penicillins.

Below is excepts from Abraham E.P. et al.: Further observations on penicillin.
Lancet. 177-188, Aug.16, 1941.
Case 1. Policeman, aged 43.

Oct.12,1940: admitted with suppuration of face, scalp and both orbits,
||||||||| starting from a sore at he corner of the mouth a month
||||||||| earlier. Primary infection Staph.aureus; secondary,Strep.pyogenes.
Dec.12 to 19: Sulphapyridine 19 g. given no improvement; drug-rash.
Jan.31, 1941: Osteomyelitis of right fumeral head, proved by Xays,
|||||||| after 3 weeks of pain; a resulting arm-abscess, incised, gave Staph.aureus pus.
Jan.21: General infection of left eye, cornea perforated
Feb. 3: eye eviscerated
Feb. 9: Blood transfusion 2 pints. Fever intermittent all this time, 98-101 F.
|||||||| Very ill and emaciated; tongue heavily furred.
Feb.11: right eye bulging and conjunctival chemosis, orbit incised, pus gave Staph.aureus
|||||||| and Strep. pyogenes.
Feb.12: all incisions suppurating, in scalp, face, both orbits, and right arm.
|||||||| Lung involved, with purulent expectoration containing both the pyogenic cocci.
|||||||| Hb 36%; red cells 1,800,000. Blood-culture sterile.
|||||||| Penicillin 200mg. given intravenously; then 100mg. 3-hourly, intravenous except
|||||||| for two intramuscular doses. Slight rigor after first dose, otherwise no reactions.
|||||||| Striking improvement after total of 800mg. penicillin in 24 hours.
|||||||| Cessation of scalp-discharge, diminution of right-eye suppuration and conjunctivitis.
|||||||| Arm discharge seems less. Blood-tests just before injections for penicillin:
|||||||| 7.30 a.m. faint trace; 11:30 a.m. none.
Feb.13: penicillin 100mg. intravenously 4-hourly.
Feb.14: condition much the same. Blood-transfusion 3 pints. peniciliin 100mg. 2- hourly
|||||||| by injection into transfusion tube; total 1.0g. in 24 hours.
Feb.15: 1 pint blood transfusion and penicillin 100mg. given 3-hourly, most of which had
|||||||| been recovered from previous urine.
Feb.16: much improvement; Hb.74%. Right eye almost normal. Some discharge still from
|||||||| left eye and arm. Shortage of penicillin interrupted treatment from noon to 6 p.m.;
|||||||| then drip-infusion of sodium chloride and citrate, pencillin 200mg. being injected
|||||||| into drip, then 100mg. 3-hourly; no reaction.
Feb.17: penicillin supply exhausted. Total administered, 4.4g.in 5 days.
|||||||| Patient felt much improved; no fever; appetite much better; resolution of infections
|||||||| in face, scalp and right orbit; still coughing; sputum contained Staph. pyogenes
|||||||| and N. catarrhalis. Left orbit and right humerus still suppurating. Blood-urea 30mg.
|||||||| per 100c.cm., urine normal.
Condition stationary for 10 days, then deteriorated, especially lungs.
March 15: died.
|||||||| Autopsy showed typical picture of staphylococcal pyaemia with multiple abscesses.

White counts.-------
Feb.12th, 20,000(polymorphs 83%)
Feb.13th, 19,000
14th, 11,200
15th, 16,800
18th, 8,400
19th, 7,600
20th, 7,600(polymorphs 84%)
25th, 8,000
March 5, 11,000(polymorhs 88%)

The attempt to treat this forlorn case was chiefly valuable in that it showed that penicillin
could be given over a period of 5 days without significant toxic effect. There was a fall
in the total white count, but both granular and a granular cells were equally affected.

Apart from this effect, which has not been seen in subsequent cases, and the slight rigor
due to a pyogenic impurity in the penicillin, no contra-indications to its use were observed.

Assessment of its effect was difficult since a blood-transfusion was given at the same time,
and later experience showed that the dose of penicillin employed was two small, and the
period of administration two short. None the less the superficial sepsis responded well,
and did not relapse after the penicillin was stopped.

Any questions: write to Keiji Hagiwara MD, keiji-hagiwara@umin.ac.jp