Alexander Fleming and Penicillin: The Accidental Discovery? By Joanna Martin.
Penicillin by Mouth
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746 may be formidable indeed. If treatment is to get a ’ fair chance, the family doctor must never finesse with a swab, but on suspicion must play the trump card of antitoxin. The bacteriological report, when it comes through, may or may not support the clinical diagnosis. This matters little, for the doctor has done the right thing for his patient. But when all is said, obviously the better way is to lower the incidence of clinical diphtheria by raising the proportion of immunes in the population as high as possible by active immunisation. Penicillin by Mouth ADMINISTRATION by mouth or rectum, if it proved ’ as effective and reliable as intramuscular injection, would make penicillin therapy simpler for the doctor and less tiresome for the patient. The research so far done has demonstrated that treatment by mouth is practicable, at least in infections by the most sensitive organisms, but, except possibly when administered in one class of vehicle, only by the expenditure of four or five times the amount of penicillin needed to obtain the same result by intramuscular or intra- venous injection or continuous infusion. The rectal route, though it has been tried,1 2 cannot be seriously considered until a way is found for protecting peni- cillin from the action of penicillinase produced by the bacteria in the lower bowel. PERLSTEIN and LIEBMANN 3 have lately prepared an anti-penicillinase serum which in vitro protected penicillin from destruction, but nothing is yet known about its activity in vivo. The vehicles tried for administration by mouth have included inorganic buffers 45 S egg,2 6 7 oils,S 8 and Romansky’s peanut-oil and beeswax mixture which was first designed for intramuscular injection.5 BURKE, Ross, and STRauss 9 enclosed sodium peni- cillin in a double gelatin capsule which was then hardened in formol and alcohol. On occasion this capsule can apparently pass through the stomach and dissolve in the duodenum, for half an hour after ingestion on an empty stomach the very high blood-level of almost 10 units per c.cm. was attained in two experiments from ’doses of 100,000 and 200,000 units. This is more than three times as high as the peak reached 15 minutes after 100,000 units intramuscularly 10 and needs confirmation. In other subjects the peak level was lower-e.g. 0-6 or 1.2 units per c.cm.-and the presence of food in the stomach diminished the effect; the highest level when the dose was taken after a meal was 2-5 units per c.cm. at half an hour and in 2 such experiments no penicillin could be detected in the blood after an hour. 1. Loewe, L., Alture-Weiber, E., Rosenblatt, P. J. Amer. med. Ass. 1945, 128, 18. 2. Barach, A. L., Garthwaite, E. T., Oppenheiner, E. T., Forman, J., Osburg, H. Science, 1945, 102, 247. 3. Perlstein, D., Liebmann, A. J. Ibid, pp. 174 and 197. 4. Rammelkamp, C. H., Keefer, C. S. J. clin. Invest. 1943, 22, 425 ; Free, A. H., Leonards, J. R., McCullagh, D. R., Biro, B. E. Science, 1944, 100, 431; Charney, J., Alburn, H. E., Bernhart, F. W. Ibid, 1945, 101, 251 ; Gyorgy, P., Vandegritt, H. N., Elias, W., Colio, L. G., Barry, F. M., Pilcher, J. D. J. Amer. med. Ass. 1945, 127, 639 ; Seeberg, V. P., Collen, M. F. Science, 1945, 102, 225. 5. McDermott, W., Bunn, P. A., Benoit, M., DuBois, R., Haynes, W. Ibid, 101, 228. 6. Little, C. J. H., Lumb, G. Lancet, 1945, i, 203. 7. Heatley, N. G. Ibid, ii, 590. 8. Libby, R. L. Science, 1945, 101, 178 ; Perlstein, D., Kluener, R. G., Liebmann, A. J., Dorrell, I. Ibid, 102, 66. 9. Burke, F. G., Ross, S., Strauss, C. J. Amer. med. Ass. 1945, 128, 83. 10. Fleming, A., Suchet, J., Young, M. Y., Rowe, A. J. E. Lancet, 1944, ii, 621. The duration of an effective blood-level in the rest, whether the penicillin was taken fasting or not, was two to four hours. This work demonstrated that under favourable circumstances absorption from the duodenum can be so fast that it overhauls the rapid excretion by the kidneys, though only for a short time. These capsules have since been used to treat gonorrhoea in children ; 11 there were no relapses in 8 patients who received four doses of 100,000 units at three-hourly intervals. Longer courses were successful in 2 patients with pneumonia and 2 with cellulitis. CUTTING and his collaborators 12 reported an investigation in which the blood-level half or one hour after a single dose, usually of 50,000 units, was the criterion of effectiveness. Besides trying various capsules and alkalis to prevent destruction by acid, they tried antiseptics with the idea of reducing destruction by penicillinase from bacteria, and they also used vehicles (organic solvents, surface- tension reducers, salicylates, quinine) which might improve absorption through the intestinal mucosa. Out of all the adjuvants investigated, three alkalis- tri-isopropanolamine, trisodium citrate, and sodium carbonate-were the only ones which were definitely useful, and there was a rather dubious benefit from lightly-coated enteric capsules. There was some evi- dence that therapeutic blood-levels were better main- tained with sodium than with calcium penicillin. From the treatment of patients with acute gonorrhoea they concluded that 500,000 units given in ten doses two-hourly in one of the more effective vehicles was a satisfactory treatment. FREE and his collaborators 13 used unhardened gelatin capsules and obtained a cure in 14 cases of gonorrhoea with the much larger total dose of 1,600,000 units. FINLAND and his colleagues 14 found that when given by mouth before meals peni- cillin was as effective in saline as in capsules and other special vehicles, but that after meals the blood-levels were irregular with all vehicles. Nevertheless, by giving 90,000 or 100,000 units two-hourly (after a larger initial dose) they maintained blood-levels high enough for the treatment of pneumonia and acute gonorrhoea. They are careful to point out, however, that infections with less sensitive organisms, such as many strains of meningococci and Staphylococcu8 aureu8 and some strains of Streptococcus ’l)iridans, cannot be treated by this method. BUNN and others 15 adopted a similar scheme of oral treatment in 45 patients with pneumococcal pneumonia, but after the first dose they gave 50,000 units two-hourly, without relation to food. In their view water was as good a vehicle as oil or gelatin capsules, and the therapeutic effect was as favourable as with parenteral treatment. Some inorganic buffers have been employed for a double purpose in penicillin therapy by mouth. It appears that aluminium hydroxide and basic alumin- ium amino-acetate will not only protect penicillin from the acid in the stomach but adsorb it and release it slowly in the intestine, so that, though the peak level 11. Ross, S., Burke, F. G., McLendon, P. A., Porter, B. V. J. Amer. med. Ass. 1945, 129, 327. 12. Cutting, W. C., Halpern, R. M., Sultan, E. H., Armstrong, C. D., Collins, C. L. Ibid, p. 425. 13. Free, A. H., Huffman, L. F., Trattner, H. R., Brown, H. B. J. Lab. clin. Med. 1945, 30, 738. 14. Finland, M., Meads, M., Ory, E. M., Wilcox, C. J. Amer. med. Ass. 1945, 129, 315. 15. Bunn, P. A., McDermott, W., Hadley, S. J., Carter, A. C, Ibid, p. 320.
Transcript of Penicillin by Mouth
746
may be formidable indeed. If treatment is to get a ’
fair chance, the family doctor must never finessewith a swab, but on suspicion must play the trumpcard of antitoxin. The bacteriological report, whenit comes through, may or may not support the clinicaldiagnosis. This matters little, for the doctor hasdone the right thing for his patient. But when all issaid, obviously the better way is to lower the incidenceof clinical diphtheria by raising the proportion ofimmunes in the population as high as possible byactive immunisation.
Penicillin by MouthADMINISTRATION by mouth or rectum, if it proved ’
as effective and reliable as intramuscular injection,would make penicillin therapy simpler for the doctorand less tiresome for the patient. The research so fardone has demonstrated that treatment by mouth ispracticable, at least in infections by the most sensitiveorganisms, but, except possibly when administeredin one class of vehicle, only by the expenditure offour or five times the amount of penicillin needed toobtain the same result by intramuscular or intra-venous injection or continuous infusion. The rectalroute, though it has been tried,1 2 cannot be seriouslyconsidered until a way is found for protecting peni-cillin from the action of penicillinase produced bythe bacteria in the lower bowel. PERLSTEIN andLIEBMANN 3 have lately prepared an anti-penicillinaseserum which in vitro protected penicillin fromdestruction, but nothing is yet known about its
activity in vivo.The vehicles tried for administration by mouth
have included inorganic buffers 45 S egg,2 6 7 oils,S 8and Romansky’s peanut-oil and beeswax mixturewhich was first designed for intramuscular injection.5BURKE, Ross, and STRauss 9 enclosed sodium peni-cillin in a double gelatin capsule which was thenhardened in formol and alcohol. On occasion thiscapsule can apparently pass through the stomachand dissolve in the duodenum, for half an hourafter ingestion on an empty stomach the very highblood-level of almost 10 units per c.cm. was attainedin two experiments from ’doses of 100,000 and200,000 units. This is more than three times as
high as the peak reached 15 minutes after 100,000units intramuscularly 10 and needs confirmation. Inother subjects the peak level was lower-e.g. 0-6 or1.2 units per c.cm.-and the presence of food in thestomach diminished the effect; the highest level whenthe dose was taken after a meal was 2-5 units perc.cm. at half an hour and in 2 such experiments nopenicillin could be detected in the blood after an hour.1. Loewe, L., Alture-Weiber, E., Rosenblatt, P. J. Amer. med. Ass.
1945, 128, 18.2. Barach, A. L., Garthwaite, E. T., Oppenheiner, E. T., Forman,
J., Osburg, H. Science, 1945, 102, 247.3. Perlstein, D., Liebmann, A. J. Ibid, pp. 174 and 197.4. Rammelkamp, C. H., Keefer, C. S. J. clin. Invest. 1943, 22, 425 ;
Free, A. H., Leonards, J. R., McCullagh, D. R., Biro, B. E.Science, 1944, 100, 431; Charney, J., Alburn, H. E., Bernhart,F. W. Ibid, 1945, 101, 251 ; Gyorgy, P., Vandegritt, H. N.,Elias, W., Colio, L. G., Barry, F. M., Pilcher, J. D. J. Amer.med. Ass. 1945, 127, 639 ; Seeberg, V. P., Collen, M. F.Science, 1945, 102, 225.
5. McDermott, W., Bunn, P. A., Benoit, M., DuBois, R., Haynes,W. Ibid, 101, 228.
6. Little, C. J. H., Lumb, G. Lancet, 1945, i, 203.7. Heatley, N. G. Ibid, ii, 590.8. Libby, R. L. Science, 1945, 101, 178 ; Perlstein, D., Kluener,
R. G., Liebmann, A. J., Dorrell, I. Ibid, 102, 66.9. Burke, F. G., Ross, S., Strauss, C. J. Amer. med. Ass. 1945,
128, 83.10. Fleming, A., Suchet, J., Young, M. Y., Rowe, A. J. E. Lancet,
1944, ii, 621.
The duration of an effective blood-level in the rest,whether the penicillin was taken fasting or not, wastwo to four hours. This work demonstrated thatunder favourable circumstances absorption from theduodenum can be so fast that it overhauls the rapidexcretion by the kidneys, though only for a shorttime. These capsules have since been used to treatgonorrhoea in children ; 11 there were no relapses in8 patients who received four doses of 100,000 unitsat three-hourly intervals. Longer courses were
successful in 2 patients with pneumonia and 2 withcellulitis. CUTTING and his collaborators 12 reportedan investigation in which the blood-level half orone hour after a single dose, usually of 50,000 units,was the criterion of effectiveness. Besides tryingvarious capsules and alkalis to prevent destructionby acid, they tried antiseptics with the idea of
reducing destruction by penicillinase from bacteria,and they also used vehicles (organic solvents, surface-tension reducers, salicylates, quinine) which mightimprove absorption through the intestinal mucosa.Out of all the adjuvants investigated, three alkalis-tri-isopropanolamine, trisodium citrate, and sodiumcarbonate-were the only ones which were definitelyuseful, and there was a rather dubious benefit fromlightly-coated enteric capsules. There was some evi-dence that therapeutic blood-levels were better main-tained with sodium than with calcium penicillin. Fromthe treatment of patients with acute gonorrhoeathey concluded that 500,000 units given in ten dosestwo-hourly in one of the more effective vehicles was asatisfactory treatment. FREE and his collaborators 13
used unhardened gelatin capsules and obtained a curein 14 cases of gonorrhoea with the much larger totaldose of 1,600,000 units. FINLAND and his colleagues 14 -
found that when given by mouth before meals peni-cillin was as effective in saline as in capsules and otherspecial vehicles, but that after meals the blood-levelswere irregular with all vehicles. Nevertheless, bygiving 90,000 or 100,000 units two-hourly (after alarger initial dose) they maintained blood-levels highenough for the treatment of pneumonia and acutegonorrhoea. They are careful to point out, however,that infections with less sensitive organisms, such asmany strains of meningococci and Staphylococcu8aureu8 and some strains of Streptococcus ’l)iridans,cannot be treated by this method. BUNN andothers 15 adopted a similar scheme of oral treatmentin 45 patients with pneumococcal pneumonia, butafter the first dose they gave 50,000 units two-hourly,without relation to food. In their view water was as
good a vehicle as oil or gelatin capsules, and thetherapeutic effect was as favourable as with parenteraltreatment.Some inorganic buffers have been employed for a
double purpose in penicillin therapy by mouth. It
appears that aluminium hydroxide and basic alumin-ium amino-acetate will not only protect penicillinfrom the acid in the stomach but adsorb it and releaseit slowly in the intestine, so that, though the peak level
11. Ross, S., Burke, F. G., McLendon, P. A., Porter, B. V. J. Amer.med. Ass. 1945, 129, 327.
12. Cutting, W. C., Halpern, R. M., Sultan, E. H., Armstrong,C. D., Collins, C. L. Ibid, p. 425.
13. Free, A. H., Huffman, L. F., Trattner, H. R., Brown, H. B.J. Lab. clin. Med. 1945, 30, 738.
14. Finland, M., Meads, M., Ory, E. M., Wilcox, C. J. Amer. med.Ass. 1945, 129, 315.
15. Bunn, P. A., McDermott, W., Hadley, S. J., Carter, A. C,Ibid, p. 320.
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in the blood will be lower than from, say, a capsulewhich discharges the penicillin rapidly in the duo-denum, an antibacterial level will be maintained con-siderably longer. The application of this principle maymake oral administration more economical and moreeffective. FINLAND and his colleagues 14 thought thataluminium hydroxide gel slightly increased and pro-longed absorption compared with other vehicles.BARACH and others 2 found that the blood-level was
higher with aluminium hydroxide than with wateralone, but they unfortunately ended their experimentsat three hours when the blood-level from 100,000units was still 0-1 units per c.cm. The improvedeffect was dependent on the penicillin being mixedwith the aluminium hydroxide before administration.A new antacid, basic aluminium amino-acetate, wastried by KRANTZ, EVANS, and McALPINE.16 Sevenhours after 100,000 units mixed with this bufferhad been given, the blood-level was 0’17 units perc.cm., the peak having been 0-68 units at three hours.No estimations later than seven hours were reported.WELCH and his collaborators 17 gave their subjects asingle dose of 100,000 units of penicillin with alumin-ium hydroxide, which they had shown would adsorbabout half the penicillin. Their composite curveof blood-levels rose to a peak of only 0-29 unit perc.cm. at half an hour, but, most remarkably, in5 out of 11 subjects penicillin could still be detectedin the blood at twenty-four hours. When the totaldose was divided into four doses of 25,000 unitsgiven two-hourly the composite curve for 21 subjectsshowed that for the first six hours of the experimentsuccessive peaks rose from 0.14 to 0-27 unit and thatfor eight hours the level did not fall below 0-08 unitper c.cm. Thereafter it gradually fell, but 0-036unit per c.cm. was still present at twenty-eighthours. In this experiment the variation betweenindividuals is not stated, but if the results wereconsistent and can be confirmed this is an importantadvance in oral administration.. Not only was thetotal dose about the same as that commonly given byintramuscular injection or infusion, but the blood-level, at least for part of the time, was higher than isusually reached by parenteral methods. By con-
tinuing two- or three-hourly administration, diseasesdue to less sensitive organisms, such as some of thenaturally resistant staphylococci, might well be
successfully treated by mouth in this way.
Internal Secretions of the KidneyTHE history of the endocrine function of the kidney
forms a striking contrast to that of its smaller neigh-bour the suprarenal. Four years after OLIVER andSCHAFER in 1894 described the pressor effects ofsaline extracts of the suprarenal gland, TIGERSTEDTand BERGMANN 18 described similar but more pro-longed effects from extracts of the cortex of therabbit’s kidney, which they attributed to the sub-stance they named renin. While adrenaline was
isolated and synthesised and its action fully investi-gated, the status of renin, and even its existence,remained so doubtful that it is not mentioned in most
16. Kranz, J. C., Evans, W. E., McAlpine, J. G. Science, 1945,101, 618.
17. Welch, H., Price, C. W., Chandler, V. L. J. Amer. med. Ass.1945, 128, 845.
18. Tigerstedt, R., Bergmann, P. G. Skand. Arch. Physiol. 1898,8, 223.
pre-war textbooks of physiology. Interest in themechanism of hypertension led, however, to its
redescription in 1938, by PICKERING and PRINZ-METAL 19 in this country, by LANDIS et all in theUnited States, and by HFss]PL 21 in Germany. Largelyas a result of the investigations of PAGE and ofHoussAY’s school in Buenos Aires it is now knownthat renin is an enzyme which acts on a serum
globulin, hypertensinogen, or renin activator, to
produce a simpler pressor substance hypertensin orangiotonin. What part renin plays in the animaleconomy is nQt yet fully known, but it seems to beconcerned with the regulation of arterial pressure,since it is released from the kidney when the renalartery is constricted,22 after the release of an occludedrenal artery,23 and when the general arterial pressureis lowered by bleeding 24 or by histamine.25
Research along physiological and biochemical lineshas thus begun to elucidate the nature and functionof renin ; but its site of origin has received less atten-tion. The recent publication by Professor GOOR-MAGHTIGH of Ghent of his anatomical researches 26 onthe endocrine function of the renal arterioles is there-fore welcome. GOORMAGHTIGH has identified alongthe course of the smaller renal arteries afibrillary cellswith a granular cytoplasm. The appearance of thegranules, their surrounding clear halo, and the presenceof marginal vacuoles ranged towards the lumen ofthe vessels, suggests the endocrine function of thesecells. In the normal kidney these cells are few andchiefly grouped in the angle formed by the efferentand afferent arterioles, the juxtaglomerular apparatus.When the circulation through the kidney is interferedwith-that is to say when the kidney is partlyinfarcted, when the renal artery is constricted, or
when the animal is rendered anaemic by successivebleedings-these afibrillary cells increase in number,apparently by transformation chiefly of the smoothmuscle cells of the media and less often of the mesan-gium of the glomerulus. In these circumstances the
secretory cells are still chiefly found in the juxta-glomerular apparatus, but they also appear in themedia and rarely in the intima of the preglomerulararterioles, and occasionally in the glomerulus itself.When the renal artery is constricted, the afibrillarycells increase in number and granularity after about24 hours. This granular reaction persists for about7 months, and then diminishes ; and after 19 monthsthe granular cells are few and altered in appearance,and degenerative changes appear in the preglomerulararterioles. The granular reaction precedes and is
roughly proportional to the rise of arterial pressure,and GOORMAGHTIGH suggests that the chemicalmediator of this form of hypertension is secreted bythe afibrillary cells. In long-continued hypertension,when the granular reaction has subsided, removal ofthe kidney does not abolish the hypertension, and it issuggested that an extrarenal factor is responsiblefor the raised pressure.
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19. Pickering, G. W., Prinzmetal, M. Clin. Sci. 1937-38, 3, 211.20. Landis, E. M., Montgomery, H., Sparkman, D. J. clin. Invest.
1938, 17, 189.21. Hessel, G. Klin. Wschr. 1938, 17, 843.22. Houssay, B. A., Braun-Menendez, E. Brit. med. J. 1942, ii, 179.23. Leo, S. D., Prinzmetal, M., Lewis, H. A. Amer. J. Physiol. 1940,
131, 18.24. Hamilton, A. S., Collins, P. A. Ibid, 1942, 136, 275.25. Huidobro, F., Braun-Menendez, E. Ibid, 1942, 137, 47.26. Goormaghtigh, N. La fonction endocrine des arterioles rénales.
1944. R. Fontcyn, Louvain. Pp. 110.
