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DEATH FROM AGRANULOCYTOSIS AFTER TREATMENT WITH PRONTOSIL FLAVUM
1519 PNEUMOCOCCUS
A small number of experiments have been performed with pneumococcus Type I. No evidence has been found that either p-aminobenzenesulphonamide or p-benzylaminobenzenesulphonamide or the disodium sulphonamide sulphonate compound has any action in preventing death in experimental infections. On the other hand both 4: 4’diaminobenzenesulphonanilide tartrate and 4:3’diaminobenzenesulphonanilide have a definite protective action. An indication of this is given in Table VI. TOXICITY IN THE HUMAN SUBJECT
Prontosil (soluble) and p-aminobenzenesulphonamide have an irritant action on the urinary tract in a large proportion of cases (Colebrook and Kenny 1936a, Foulis and Barr 1937); sulpheemoglobinaemia is also common (Colebrook and Kenny 1936a, Foulis and Barr 1937, Paton and Eaton 1937). In the human subject no cases of nervous-system complications, such as occur in mice, have been reported, but one such has come to my knowledge. No cases of sulphaemoglobinsemia occurred during the treatment of 215 cases of streptococcal infection with p-benzylaminobenzenesulphonamide by Peters and Havard (1937), nor have any been observed in my own experience of some 20 cases. Nausea and vomiting are seen occasionally with all three
preparations. DISCUSSION
The aim of any therapeutic procedure is to combine efficiency with safety. The efficiency of the various compounds available for the treatment of streptococcal infections is summarised in Table VI where the known toxic doses for mice are also stated. The most common complications with p-aminobenzenesnlphonamide are sulphaemoglobinsemia and methsemoglobinsemia and though there appears to have been very little mortality from these complications they cannot be regarded as a desirable burden for even a convalescent patient to bear. p-benzylaminobenzenesulphonamide would appear less likely to produce these complications both from experimental evidence and from clinical report ; the substance is equally active and is therefore worthy of clinical trial. As to the soluble compounds there is again a bigger margin of safety with disodium-p (y-phenyl-propylamino) benzenesulphonamide-a-y-disulphonate than with prontosil (soluble) as judged from animal experiment. And, in my own experience, I have given 20 c.cm. of the first-named compound daily for five days by the intravenous route without the slightest toxic symptom ; experimentally there is nothing to choose between the efficiency of the two compounds. It should be noted that p-benzylaminobenzenesulphonamide and the soluble disodium sulphonamide sulphonate compound are both inactive in meningococcal infections, whilst p-aminobenzenesulphonamide is active. All three compounds are quite inactive in pneumococcal infections. SUMMARY
(1) The oral preparations, p-benzylaminobenzenesulphonamide and p-aminobenzenesulphonamide, are equally effective in experimental streptococcal infections. The former is very much less toxic than the latter. (2) Of preparations for injection, prontosil (soluble) and disodium-p (y-phenyl-propyl-amino) benzenesulphonamide (x-y-disulphonate are equally effective in experimental streptococcal infections ; the latter is less toxic than the former.
(3) p-amino benzenesulphonamide is effective in experimental meningococcal infections. p-benzylamino benzenesulphonamide and disodium-p (y-phenylpropyl-amino) benzenesulphonamide-a-y-disulphonate are
inactive.
(4) Two diaminobenzenesulphonanilide compounds have been found to have a considerable polyvalent action ; they are well tolerated and one protects against streptococcus, pneumococcus, and meningococcus, the other against streptococcus and pneumococcus.
I am greatly indebted to Messrs. May and Baker Limited for supplies of p-benzylaminobenzenesulphonamide (Proseptasine), of disodium-p (’y-phenyl-propyl-
amino) benzenesulphonamide-a--y-disulphonate (Soluseptasine), and of the other experimental products referred to in this paper. REFERENCES
Becker, W. (1937) Derm. Wschr. 104, 221. Bloch-Michel, H., Conte, M., and Durel, P. (1936) Pr. méd. 44, 1583. Buttle, G. A. H., Parish, H. J., McLeod, M., and Stephenson, D. (1937) Lancet, 1, 681. Colebrook, L., and Kenny, M. (1936a) Ibid, 1, 1279. (1936b) Ibid, 2, 1319. Foulis, M. A., and Barr, J. B. (1937) Brit. med. J. 1, 445. Halpern, B. N., and Mayer, R. L. (1937) Pr. méd. 45, 747. Medizin und Chemie (1936) 3, 24 (Bayer). Paton, J. P. J., and Eaton, J. C. (1937) Lancet, 1, 1159. Peters, B. A., and Havard, R. V. (1937) Ibid, 1, 1273. Proom, H. (1937) Ibid, 1, 16. Schwentker, F. F., Gelman, S., and Long, P. H. (1937) J. Amer. med. Ass. 108, 1407. —
—
DEATH FROM AGRANULOCYTOSIS AFTER TREATMENT WITH PRONTOSIL FLAVUM BY J. G. G.
BORST, M.D.
SENIOR ASSISTANT IN THE INTERNAL HOSPITAL DEPARTMENT OF MEDICINE, UNIVERSITY OF AMSTERDAM
ALTHOUGH the benzenesulphonamide introduced only a few years ago they
compounds are already widely used. Originally they were given only in streptococcal infections, but lately they have also been recommended for meningococcal infections1 and pyelocystitis.2 It soon became clear, however, that they were liable to have serious toxic effects, and cases of sulphaemoglobinaemia,3 methaemoglobineamia,4 and nitritoid crisis5 have been reported. Between September and December, 1936, I treated 13 cases of B. coli pyelocystitis with Prontosil Flavum, and 5 of these developed toxic symptoms. One patient became dyspnaeic and developed CheyneStokes respiration ; she was seriously ill for one day, but not cyanotic. As in September I had not yet were
read Colebrook’s article3did not test the blood for sulphaemoglobin and methaemoglobin ; the number of leucocytes and the differential leucocyte count Three patients complained of paraeswere normal. thesiae in the face and of the hands : two of them at the same time had sensory disturbances ; while doing their hair they could not actually feel it. None :)f these patients received more than six tablets of 300 mg. prontosil flavum daily, and after discontinuing administration of the drug the symptoms lisappeared in a few days. The fifth patient developed agranulocytosis. She was a woman of 61, and was taken into the wards Nov. 21st, 1936, for pyelocystitis. In 1925 and 1926 i ihe had been treated in the gynaecological wards for j laemorrhagic discharge and gum-bleeding, while blue )n
1520
patches were showing on her arms also. The treatment percussion of the left lower lobe accompanied by bronchial given included curettage, irradiation of the spleen breath sounds, the temperature rising to 39° C. (1022° F.). with X rays, injection of horse-serum of the patient’s Prontosil treatment was discontinued. A blood count on A diagnosis of thrombopenic own blood, and of gelatin. Dec. 30th showed : haemoglobin, 70 per cent. ; red cells, 3,330,000 (slight anisocytosis) ; reticulocytes, 0-8 per purpura was made. (A complete history of the case is unfortunately not available.) In 1929 she was examined cent. ; platelets (of normal appearance under the microin the out-patient department of Prof. Ruitinga, becausescope), 270,000 per c.mm. ; white cells, 1225 (eosinophils 0, she had a few petechiae on her legs. A blood count showed : basophils 2tper cent., polymorphonuclears, 2per cent., red cells, 4,420,000 per c.mm. ; haemoglobin, 83 per cent. ; lymphocytes 83i per cent., monocytes 11 per cent.), platelets, slightly increased (estimated roughly) ; white That same evening the patient had difficulty in swallowing. cells, 10,500 per c.mm. (eosinophils 2 per cent., basophils the throat being slightly red. On the morning of Dec. 31st It per cent., stab cells 7 per cent., polymorphonuclears the number of leucocytes had dropped to 960 per c.mm., 45tper cent., lymphocytes 37 per cent., monocytes the differential count being polymorphonuclears 1 per cent., 7 per cent.). No important symptoms of disease developed lymphocytes 87 per cent., monocytes 12 per cent. In then
the afternoon the mortem
Temperature and pulse chart showing dosage of prontosil flavum administered (1°8 g. and 2’4g. daily).
1929, and the patient suffered from nothing except frequency of micturition. A fortnight before admission pains in the loins and strangury developed, the urine becoming cloudy and foul. On admission on Nov. 21st her temperature was 39° C. (102° F.). Nothing abnormal was found in lungs, heart, or abdomen. The urine contained2 per mille albumin, after
and was full of pus and coli bacilli. A blood count on Nov. 23rd showed 8000 white cells per e.mm. (eosinophils 2 per cent., metamyelocytes (juveniles) 1 per cent., stab cells 12 per cent., polymorphonuclears 51 per cent., lymphocytes 11 per cent., plasma cells 7 per cent., and monocytes 16 per cent. The Wassermann and Sachs-Georgi test were negative, the sedimentation-rate of the blood was 83 mm. in the first hour. From Nov. 21st till Dec. 3rd the patient received daily six tablets of 300 mg. prontosil flavum. At first the temperature dropped, but after a few days it rose again to 39° C. (see Chart), though the urine contained neither leucocytes nor bacteria, and a culture remained sterile. The patient had no complaint. The prontosil treatment was discontinued, the temperature dropped, but leucocytes and coli bacilli reappeared in the urine ; and after a few days the temperature went up again. On Dec. llth prontosil treatment was resumed ; but half an hour after taking the first two tablets the patient had cold shivers, the temperature rising to 40° C. (104° F.). The blood showed the full picture of infection with 14,000 white cells (polymorphonuclears 62 per cent., stab cells 28 per cent., metamyelocytes (juveniles) 2 per cent.’ lymphocytes 1 per cent., and monocytes 13 per cent.)’ The number of platelets, roughly estimated, was normal. Haemoglobin 78 per cent. The patient complained of pain in the left side, and there was much tenderness on pressure in the region of the left kidney. From Dec. llth to 21st the patient again received six tablets of prontosil flavum daily; and again the leucocytes and bacteria disappeared from the urine within a few days, while the temperature dropped. But this time also the temperature did not become quite normal, as it varied between 37-2 and 37.80 C. As I suspected that, although the urine was sterile, the infection of the kidney itself had not yet been cured, I increased the dose of prontosil to eight tablets daily on Dec. 22nd. On Dec. 28th the patient complained of general discomfort, the temperature in the evening being 38.1° C. (100-5° F.). No special attention was paid to this because there was an outbreak of influenza among the other patients, four of nine women in the ward having temperatures above 38° C. On Dec. 29th the patient showed tympanic
marrow
were
(as
patient
ateiectasis
or
died. Post.
me
ten iower
lobe was found; no signs of pneu. monia were apparent either naked-eye or on microscopical examination. Also the angina was not demonstrable any more ; it certainly had not been severe during life. There were no more signs of inflammation of the bladder and left and right pelvis ; sections of the kidneys showed a few small round-cell infiltrations in the medulla; otherwise kidneys were normal. No abnormali. ties to account for the high tempera. ture and death were found. As the autopsy took place 28 hours after the films .L.l.U.1.l0 taken lJQ.l&bgr;..O.L.Lfrom .l.LV.ll..1 the umv boneUU.lJ.Cdeath, U.1.10 UOQ./lJ.1.1, was expected) unsuitable for drawing
any conclusions.
stay in the wards this patient had no except prontosil flavum, some dilute hydrochloric acid to facilitate its absorption, and (on Dec. 10th) 15 grammes of castor oil. There can
During
her
remedies
I think be no doubt about the close connexion between the use of prontosil flavum and the occurrence of agranulocytosis in this case, but the patient’s unusual previous history may indicate some predisposing disease of the bone-marrow. It is not clear why so many of the 13 patients in this series showed toxic symptoms during prontosil treatment. With 2 exceptions, none of the patients were seriously ill before they were treated ; during the whole course of their illness 9 had had no fever. Prontosil flavum is generally given to patients suffering from streptococcal sepsis, and where the illness is already severe slight symptoms of intoxication are not easily recognised, so that even a serious complication like agranulocytosis may not alter the clinical picture radically enough to attract attention. In the case recorded here the first diagnosis was one of influenzal pneumonia. As a result of our unfavourable experience prontosil flavum treatment was stopped, but in 11 more
p-aminobenzenesulphonamide (Prontosil Album) given. This drug also caused toxic effects, but these were fairly harmless. In all patients feeling ill or having fever, the blood was repeatedly examined, but no qualitative or quantitative abnormalities of the leucocytes were found. cases
was
REFERENCES 1. Buttle, G. A. H., Gray, W.
H., and Stephenson, D. (1936) Lancet, 1, 1286 ; Proom, H. (1937) Ibid, 1, 16 ; Schwentker, F. F., Gelman, S., Long, P. H. (1937) J. Amer. med. Ass. 108, 1407. 2. Imhaüser, K. (1935) Med. Klin. 31, 282 ; Huber, H. G. (1936) Münch. med. Wschr. 3, 2014 ; Unshelm, E. (1936) Arch. Kinderheilk. 109, 66. 3. Colebrook, L., and Kenny, M. (1936) Lancet, 1, 1279; Frost, L. D. B. (1937) Ibid, 1, 510 ; Discombe, G. (1937) Ibid, 1, 626. 4. Paton, J. P. J., and Eaton, A. I. C. (1937) Ibid, 1, 1159 and 1369. 5.
Sézary, A., and Friedmann, Paris, 52, 636.
E.
(1936) Bull. Soc. méd. Hôp.
A small number of experiments have been performed with pneumococcus Type I. No evidence has been found that either p-aminobenzenesulphonamide or p-benzylaminobenzenesulphonamide or the disodium sulphonamide sulphonate compound has any action in preventing death in experimental infections. On the other hand both 4: 4’diaminobenzenesulphonanilide tartrate and 4:3’diaminobenzenesulphonanilide have a definite protective action. An indication of this is given in Table VI. TOXICITY IN THE HUMAN SUBJECT
Prontosil (soluble) and p-aminobenzenesulphonamide have an irritant action on the urinary tract in a large proportion of cases (Colebrook and Kenny 1936a, Foulis and Barr 1937); sulpheemoglobinaemia is also common (Colebrook and Kenny 1936a, Foulis and Barr 1937, Paton and Eaton 1937). In the human subject no cases of nervous-system complications, such as occur in mice, have been reported, but one such has come to my knowledge. No cases of sulphaemoglobinsemia occurred during the treatment of 215 cases of streptococcal infection with p-benzylaminobenzenesulphonamide by Peters and Havard (1937), nor have any been observed in my own experience of some 20 cases. Nausea and vomiting are seen occasionally with all three
preparations. DISCUSSION
The aim of any therapeutic procedure is to combine efficiency with safety. The efficiency of the various compounds available for the treatment of streptococcal infections is summarised in Table VI where the known toxic doses for mice are also stated. The most common complications with p-aminobenzenesnlphonamide are sulphaemoglobinsemia and methsemoglobinsemia and though there appears to have been very little mortality from these complications they cannot be regarded as a desirable burden for even a convalescent patient to bear. p-benzylaminobenzenesulphonamide would appear less likely to produce these complications both from experimental evidence and from clinical report ; the substance is equally active and is therefore worthy of clinical trial. As to the soluble compounds there is again a bigger margin of safety with disodium-p (y-phenyl-propylamino) benzenesulphonamide-a-y-disulphonate than with prontosil (soluble) as judged from animal experiment. And, in my own experience, I have given 20 c.cm. of the first-named compound daily for five days by the intravenous route without the slightest toxic symptom ; experimentally there is nothing to choose between the efficiency of the two compounds. It should be noted that p-benzylaminobenzenesulphonamide and the soluble disodium sulphonamide sulphonate compound are both inactive in meningococcal infections, whilst p-aminobenzenesulphonamide is active. All three compounds are quite inactive in pneumococcal infections. SUMMARY
(1) The oral preparations, p-benzylaminobenzenesulphonamide and p-aminobenzenesulphonamide, are equally effective in experimental streptococcal infections. The former is very much less toxic than the latter. (2) Of preparations for injection, prontosil (soluble) and disodium-p (y-phenyl-propyl-amino) benzenesulphonamide (x-y-disulphonate are equally effective in experimental streptococcal infections ; the latter is less toxic than the former.
(3) p-amino benzenesulphonamide is effective in experimental meningococcal infections. p-benzylamino benzenesulphonamide and disodium-p (y-phenylpropyl-amino) benzenesulphonamide-a-y-disulphonate are
inactive.
(4) Two diaminobenzenesulphonanilide compounds have been found to have a considerable polyvalent action ; they are well tolerated and one protects against streptococcus, pneumococcus, and meningococcus, the other against streptococcus and pneumococcus.
I am greatly indebted to Messrs. May and Baker Limited for supplies of p-benzylaminobenzenesulphonamide (Proseptasine), of disodium-p (’y-phenyl-propyl-
amino) benzenesulphonamide-a--y-disulphonate (Soluseptasine), and of the other experimental products referred to in this paper. REFERENCES
Becker, W. (1937) Derm. Wschr. 104, 221. Bloch-Michel, H., Conte, M., and Durel, P. (1936) Pr. méd. 44, 1583. Buttle, G. A. H., Parish, H. J., McLeod, M., and Stephenson, D. (1937) Lancet, 1, 681. Colebrook, L., and Kenny, M. (1936a) Ibid, 1, 1279. (1936b) Ibid, 2, 1319. Foulis, M. A., and Barr, J. B. (1937) Brit. med. J. 1, 445. Halpern, B. N., and Mayer, R. L. (1937) Pr. méd. 45, 747. Medizin und Chemie (1936) 3, 24 (Bayer). Paton, J. P. J., and Eaton, J. C. (1937) Lancet, 1, 1159. Peters, B. A., and Havard, R. V. (1937) Ibid, 1, 1273. Proom, H. (1937) Ibid, 1, 16. Schwentker, F. F., Gelman, S., and Long, P. H. (1937) J. Amer. med. Ass. 108, 1407. —
—
DEATH FROM AGRANULOCYTOSIS AFTER TREATMENT WITH PRONTOSIL FLAVUM BY J. G. G.
BORST, M.D.
SENIOR ASSISTANT IN THE INTERNAL HOSPITAL DEPARTMENT OF MEDICINE, UNIVERSITY OF AMSTERDAM
ALTHOUGH the benzenesulphonamide introduced only a few years ago they
compounds are already widely used. Originally they were given only in streptococcal infections, but lately they have also been recommended for meningococcal infections1 and pyelocystitis.2 It soon became clear, however, that they were liable to have serious toxic effects, and cases of sulphaemoglobinaemia,3 methaemoglobineamia,4 and nitritoid crisis5 have been reported. Between September and December, 1936, I treated 13 cases of B. coli pyelocystitis with Prontosil Flavum, and 5 of these developed toxic symptoms. One patient became dyspnaeic and developed CheyneStokes respiration ; she was seriously ill for one day, but not cyanotic. As in September I had not yet were
read Colebrook’s article3did not test the blood for sulphaemoglobin and methaemoglobin ; the number of leucocytes and the differential leucocyte count Three patients complained of paraeswere normal. thesiae in the face and of the hands : two of them at the same time had sensory disturbances ; while doing their hair they could not actually feel it. None :)f these patients received more than six tablets of 300 mg. prontosil flavum daily, and after discontinuing administration of the drug the symptoms lisappeared in a few days. The fifth patient developed agranulocytosis. She was a woman of 61, and was taken into the wards Nov. 21st, 1936, for pyelocystitis. In 1925 and 1926 i ihe had been treated in the gynaecological wards for j laemorrhagic discharge and gum-bleeding, while blue )n
1520
patches were showing on her arms also. The treatment percussion of the left lower lobe accompanied by bronchial given included curettage, irradiation of the spleen breath sounds, the temperature rising to 39° C. (1022° F.). with X rays, injection of horse-serum of the patient’s Prontosil treatment was discontinued. A blood count on A diagnosis of thrombopenic own blood, and of gelatin. Dec. 30th showed : haemoglobin, 70 per cent. ; red cells, 3,330,000 (slight anisocytosis) ; reticulocytes, 0-8 per purpura was made. (A complete history of the case is unfortunately not available.) In 1929 she was examined cent. ; platelets (of normal appearance under the microin the out-patient department of Prof. Ruitinga, becausescope), 270,000 per c.mm. ; white cells, 1225 (eosinophils 0, she had a few petechiae on her legs. A blood count showed : basophils 2tper cent., polymorphonuclears, 2per cent., red cells, 4,420,000 per c.mm. ; haemoglobin, 83 per cent. ; lymphocytes 83i per cent., monocytes 11 per cent.), platelets, slightly increased (estimated roughly) ; white That same evening the patient had difficulty in swallowing. cells, 10,500 per c.mm. (eosinophils 2 per cent., basophils the throat being slightly red. On the morning of Dec. 31st It per cent., stab cells 7 per cent., polymorphonuclears the number of leucocytes had dropped to 960 per c.mm., 45tper cent., lymphocytes 37 per cent., monocytes the differential count being polymorphonuclears 1 per cent., 7 per cent.). No important symptoms of disease developed lymphocytes 87 per cent., monocytes 12 per cent. In then
the afternoon the mortem
Temperature and pulse chart showing dosage of prontosil flavum administered (1°8 g. and 2’4g. daily).
1929, and the patient suffered from nothing except frequency of micturition. A fortnight before admission pains in the loins and strangury developed, the urine becoming cloudy and foul. On admission on Nov. 21st her temperature was 39° C. (102° F.). Nothing abnormal was found in lungs, heart, or abdomen. The urine contained2 per mille albumin, after
and was full of pus and coli bacilli. A blood count on Nov. 23rd showed 8000 white cells per e.mm. (eosinophils 2 per cent., metamyelocytes (juveniles) 1 per cent., stab cells 12 per cent., polymorphonuclears 51 per cent., lymphocytes 11 per cent., plasma cells 7 per cent., and monocytes 16 per cent. The Wassermann and Sachs-Georgi test were negative, the sedimentation-rate of the blood was 83 mm. in the first hour. From Nov. 21st till Dec. 3rd the patient received daily six tablets of 300 mg. prontosil flavum. At first the temperature dropped, but after a few days it rose again to 39° C. (see Chart), though the urine contained neither leucocytes nor bacteria, and a culture remained sterile. The patient had no complaint. The prontosil treatment was discontinued, the temperature dropped, but leucocytes and coli bacilli reappeared in the urine ; and after a few days the temperature went up again. On Dec. llth prontosil treatment was resumed ; but half an hour after taking the first two tablets the patient had cold shivers, the temperature rising to 40° C. (104° F.). The blood showed the full picture of infection with 14,000 white cells (polymorphonuclears 62 per cent., stab cells 28 per cent., metamyelocytes (juveniles) 2 per cent.’ lymphocytes 1 per cent., and monocytes 13 per cent.)’ The number of platelets, roughly estimated, was normal. Haemoglobin 78 per cent. The patient complained of pain in the left side, and there was much tenderness on pressure in the region of the left kidney. From Dec. llth to 21st the patient again received six tablets of prontosil flavum daily; and again the leucocytes and bacteria disappeared from the urine within a few days, while the temperature dropped. But this time also the temperature did not become quite normal, as it varied between 37-2 and 37.80 C. As I suspected that, although the urine was sterile, the infection of the kidney itself had not yet been cured, I increased the dose of prontosil to eight tablets daily on Dec. 22nd. On Dec. 28th the patient complained of general discomfort, the temperature in the evening being 38.1° C. (100-5° F.). No special attention was paid to this because there was an outbreak of influenza among the other patients, four of nine women in the ward having temperatures above 38° C. On Dec. 29th the patient showed tympanic
marrow
were
(as
patient
ateiectasis
or
died. Post.
me
ten iower
lobe was found; no signs of pneu. monia were apparent either naked-eye or on microscopical examination. Also the angina was not demonstrable any more ; it certainly had not been severe during life. There were no more signs of inflammation of the bladder and left and right pelvis ; sections of the kidneys showed a few small round-cell infiltrations in the medulla; otherwise kidneys were normal. No abnormali. ties to account for the high tempera. ture and death were found. As the autopsy took place 28 hours after the films .L.l.U.1.l0 taken lJQ.l&bgr;..O.L.Lfrom .l.LV.ll..1 the umv boneUU.lJ.Cdeath, U.1.10 UOQ./lJ.1.1, was expected) unsuitable for drawing
any conclusions.
stay in the wards this patient had no except prontosil flavum, some dilute hydrochloric acid to facilitate its absorption, and (on Dec. 10th) 15 grammes of castor oil. There can
During
her
remedies
I think be no doubt about the close connexion between the use of prontosil flavum and the occurrence of agranulocytosis in this case, but the patient’s unusual previous history may indicate some predisposing disease of the bone-marrow. It is not clear why so many of the 13 patients in this series showed toxic symptoms during prontosil treatment. With 2 exceptions, none of the patients were seriously ill before they were treated ; during the whole course of their illness 9 had had no fever. Prontosil flavum is generally given to patients suffering from streptococcal sepsis, and where the illness is already severe slight symptoms of intoxication are not easily recognised, so that even a serious complication like agranulocytosis may not alter the clinical picture radically enough to attract attention. In the case recorded here the first diagnosis was one of influenzal pneumonia. As a result of our unfavourable experience prontosil flavum treatment was stopped, but in 11 more
p-aminobenzenesulphonamide (Prontosil Album) given. This drug also caused toxic effects, but these were fairly harmless. In all patients feeling ill or having fever, the blood was repeatedly examined, but no qualitative or quantitative abnormalities of the leucocytes were found. cases
was
REFERENCES 1. Buttle, G. A. H., Gray, W.
H., and Stephenson, D. (1936) Lancet, 1, 1286 ; Proom, H. (1937) Ibid, 1, 16 ; Schwentker, F. F., Gelman, S., Long, P. H. (1937) J. Amer. med. Ass. 108, 1407. 2. Imhaüser, K. (1935) Med. Klin. 31, 282 ; Huber, H. G. (1936) Münch. med. Wschr. 3, 2014 ; Unshelm, E. (1936) Arch. Kinderheilk. 109, 66. 3. Colebrook, L., and Kenny, M. (1936) Lancet, 1, 1279; Frost, L. D. B. (1937) Ibid, 1, 510 ; Discombe, G. (1937) Ibid, 1, 626. 4. Paton, J. P. J., and Eaton, A. I. C. (1937) Ibid, 1, 1159 and 1369. 5.
Sézary, A., and Friedmann, Paris, 52, 636.
E.
(1936) Bull. Soc. méd. Hôp.