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Thiosemicarbazone in chemotherapy of tuberculosis
October 1951
217
Thiosemicarbazone in Chemotherapy of Tuberculosis Report of Pilot Trial organized by the Research Committee of the British TuberculosisAssociation This paper attempts a review of the present status of thiosemicarbazone therapy in tuberculosis and makes a report on a small pilot trial carried out in this country u n d e r the auspices of the Research Committee oF tile British Tuberculosis Association. The pioneer work on thioscmicarbazone was performed by Domagk [t] and his colleagues in Germany. He reported in i946 that of a number of thiosemicarbazones p-acetylaminobenzaldehyde thioscmicarbazone (T.B.I [698 ) was tile most active against the M. tuberculosis in vitro and in experimental animals. It appeared to have a different mode of.action from streptomycin and PAS and not to be antagonized by para-alnino9benzoic acid. In vitro and in guinea-pig infection, T.B.I was weight for weight more efficacious than PAS, even in a dose Ioo times smaller than the latter. Domagk later reported that it inhibits growth on culture m e d i u m containing p-aminobenzoic acid at three times as high a dilution as even streptomycin [2]. Since I946. other workers have examined the thiosemicarbazones and it would seem that T.B.I is not as effective (at any rate in tuberculous infection of mice) as p-ethylsulphonylbenzaldehyde thiosemicarbazone (T.B.III in Germany) [3, 4] which in this content was more highly active than PAS and even superior to streptomycin in the early stages of disease. On the other hand, Spain, Childress and Fishler [5] found that T.B.I (Tibione) also could be favourably compared with streptomycin in treating tuberculosis in guinea-pigs. At any rate, all the clinical trials so far have been concerned with tile use of T.B.I. In October I949 Mertens and Bunge reported that 'far more than IO,OOO patients had been treated and over 6o clinical papers published or pending in Germany' [6]. The favourable results reported were placed in focus by Hinshaw and McDermott [7] who in I95O on behalf of the National Tuberculosis Association of America visited 8 insti-
tutions in Germany. There was an absence of controls and often the periods of observation were short, the use o f paper films sometimes made assessment difficult and in any case evaluation of this type of therapy against tuberculosis in a general population recovering from a period of malnutrition was bound to be difficult. The popularity of T.B.I in Germany was probably influenced in its early stages by its low cost of production compared with high price (in dollars) of streptomycin and PAS. All the reports imply that T.B.I, like other antibiotics, in pulmonary tuberculosis affects favourably the more labile lesions. Sturm [8] for instance reports on x 17 cases so trcated and Klee [9] on 200 cases treated for thirty months. As well as being slower in action than streptomycin, T.B.I is also less certain, however, even in such favourable lesions. Extensive caseation and chronic disease respond little. Acute miliary tuberculosis and tuberculous meningitis are not influenced and this may be due to the slower onset of the thiosemicarbazone effect (Mertens and ,Bunge [6]). Tile alleged favourable effect of T.B. I on mucosal tuberculosis may account for changes which have bccn reported in softwalled and distension cavities. Mertens and Bunge emphasized that recession of a cavity may not be permanent if T.B.I is stopped too soon and that it should be continucd for at least six months. In addition to .or instead of peroral thiosemicarbazone, the drug has been instilled into cavities undergoing drainage (Wilde 'and Ruck [IO]) and good results reported. It has been estimated that T.B.x. will influence favourably 80 per cent or more of cases of tuberculous laryngitis (Arold [ I I, I ~]) and many cases of ulceration of the tongue. Tuberculosis of the intestines and of tile bladder and ureter and urethra will also respond. Papers read at the 55th Congress of Internal Medicine held at Wiesbaden in
218
T U B ERC L E
I949 emphasize the place given to T.B.I by the Germans in these various forms of tuberculosis. The beautifully produced monograph published in German in I95O under the editorship of G. Domagk brings together the views of leading workers in his country. In this country, published work has been sparse. Dunn [i4] , Bavin et al. [i5] , Hogarth and Martin [I6] have all reviewed the pharmacological aspects. The only clinical paper has been one by Livingstone and Street [I7] reporting on a small series Of uncontrolled cases treated by the drug. It is certain, however, that a number of clinicians have been using it, perhaps sometimes rather haphazardly. Moesehlin and Demiral [~8] concluded on experimental evidence that the activity of T.B.I was somewhat less than that of PAS, that combining streptomycin and the former drug was no improvement on the use of streptomycin alone and that streptomycin and PAS was undoubtedly the best combination. Dosage: In contradistinction to laboratory animals, in which tlfiosemicarbazones are relatively poorly absorbed, T.B.I is not tolerated well by human beings and after a preliminary period in which higher doses were used, most clinicians now do not exceed .ooo rag. a day. A dose of 2 rag. per kilo body-weight has been recommended, but it is probable that this can be exceeded in many cases without incurring side-effects. In any event, the maximum dose should be reached by gradual increases from a preliminary 5 ~ mg. a day.
Complications T h a t T.B.I may have toxic effects was reported by the German workers. Simmons and his colleagues [I9] adnfinistered the drug (Myvizone) in large doses (up to a maximum of 8oo nag. a day) to I6 patients, most of whom had untoward symptoms, including disturbed liver fimction and it was, however, interesting that the side-effects were not more severe or permanent. The
October 1951
toxic phenomena reported by the Germans largely date back to a period when the preparation was given in a combination with sulphathiazole (Eleudron) or when the doses were larger than are usual now. Domagk [I] detailed the following: (I) Gastro-intestinal complications - disturbed appetite and nausea. Vomiting occurring later in the course should lead to discontinuation of T.B.x. (2) Allergic phenomena - mild conjunctival irritation and possibly exanthenaata of various types including severe lmemorrhagic forms. (3) Haematopoietic changes-occasionally on agranulocytosis (hIertens and Bunge dcscribe an allergic form with eosinophilia) which may be ushered in with an increase in fever. Haemolyric anaemia may occur. (4) Renal d a m a g e - aibunainuria, usually disappears spontaneously or when drug is stopped. (5) Liver d a m a g e - with jaundice, strong urobilinogen reaction, positive Takata-Ara test and other signs (Mertens and Bunge throw doubt on hepatotoxicity as being due to T.B.I in present doses). (6) Eneephalopathy - increased intracranial pressure, with headache. Probably unlikely with present doses. The early reports of such toxic effects gave the impression that thiosemicarbazone was an unusually poisonous substance. Since, however, it had received such praise from German workers and was becoming available in this country, the B.T.A. Research Committee decided to attempt a pilot trial as a prelude to it possible more scientific investigation on a wider scale. The following account is of the foriner. It should be stressed that when it was envisaged tim Committee was by no means convinced by the German figures but more impressed by the reported toxic effects, so the pilot trial was to a great extent designed to confirm the safety of the so-called 'safe' doses, whilst using individuals with a type of
October 1951
disease for which, streptomycin immediately indicated.
T U BERC L E
was not
Pilot Trial 9For the reason given in the previous paragraph, the type of case prescribed had chronic, bilateral fibrocaseous disease with some radiological shadows that might be judged likely to response to an antibiotic. This definition was observed in most instances though (especially in the Grove Park patients) T.B.z was sometimes given for specific indications, e.g. laryngitis or an isolated distension cavity or abdominal involvement. In all, 45 cases were reviewed, the results being assessed by the individual clinicians and summarized centrally from their reports. T h e following description has been deliberately kept brief in order not to appear to overstress a trial carried out on, for the most part, unfavourable cases over what might be claimed to be an inadequate period. Five institutions participated-Broomfield Hospital, Liverpool Sanatorium, Poole Sanatorium, King George V Sanatorium and" Grove Park Hospital. The drug (Conteben) was given orally, at first in graduated doses fi'om 25 to 5 ~ mg. a day up to an effective dose of fi'om 2 nag. per kilo body-weight to 0.5o mg. a day. A course of four months had been prescribed and more than half the cases finished that period or longer (three or five months, o for six months), but 9 had only three months and some as little as two months, the course having been interrupted because of complications or general deterioration or because 'collapse therapy became practicable and desirable. A very small uumber of patients had been observed for less than two months and many for much longer (2x for four months or more); changes in that time were taken into account in assessing results of treatment. X-ray Changes The table gives results in 25 patients who had T.B.I, primarily for pulmonary lesions, for at least four months. In I0. there was
219
x-ray improvement which might be attributed to the drug and the most frequent effect seemed to be on cavities. There were favourable changes in others who had T.B.I for less than four months. O f 9 so treated for between three and four months, four showed significant improvement. General Effects Though a proportion of patients showed improvement in general well-being, appetite and weight, this could not ahvays be correlated with radiological change and was lcss marked than that which many observers have found to accompany administration of PAS. The same can be said with regard to changc in tile E.S.R. Neither was there any constant effect on temperature. O f the 25 cases treated for four months or more, I was sputum negative throughout and of the remainder, there were only 5 conversions to negative. Effects on Complications (z) Laryngeal tuberculosis (9 cases). 4 showed marked and 3 moderate improvement. The former were no doubt affected by administratiou of T.B.I, but in the latter this cannot be deduced, except perhaps in one patient Who had an 'allergic' reaction (see below) and in whom in the eleven days before the drug was discontinued had shown a definite improvement with regard to the laryngeal condition. (2) Tuberculous enteritis (2 cases). In one patient the condition was terminal and no conclusions can be drawn as he had gross disease elsewhere and died. The other (at Broomfield Hospital) was a man of 33, who had had pulmonary tuberculosis for approxinmtely two years. The ltmgs showed mainly Icft-sided disease with cavities in the upper half, one of them moderately large. His general condition was poor, with evening pyrexia (99 ~) and continual complaints of dyspepsia and bouts of diarrhoea and general dispiritedness. Conteben had a marked effect on all general symptoms: fall of temperature to normal
220
T U BERC LE TAB
October 1951
LE
Case
Age
Disease
Obs.
Change dur. obs.
Dur. of T.B. I
I 2 3
24 34 35
8 mos. 6 mos.
N.C . . . . . S1. l a r g e r .-
4 mos. 5 mos.
C. s m a l l e r G. s m a l l e r
I2 mos.
G. imp. in R U Z
4 mos.
G. s m a l l e r
4
25
Tens. C. L U L . . . . . do . . . . . "Fens. C. R U L . , Chr. dis. RUZ & RhlZ... Chr. dis. R. h m g 2 large C. L U Z . . . . .
I2 mos.
Tendency to spread N.C . . . . .
6mos. 5 mos.
G. imp., one much smaller C. s m a l l e r
Spr. L. l u n g
..
4 mos.
C. almost gone
Resistant t o S / M Resistant t o S / M
4 mos. 4 mos.
N.C. N.C.
Little eh.
4 mos.
N 9149
5 6
3x 31
7
26
98 9
33 3I
io
44
II
39
x2
35
13
27
14
2~
15
29
16
38
x7
26
x8
19
I8
33
20
5~
2x
44
22
43
2 Tens. C. L U Z . . . . 7 raGS. S c a t t e r e d dis. L . h m g . C. b l o w n u p L U L . . 3 mos. Bilat. exud. dis. w i t h recent C.s .. 8 4 days T ' p l a s t y R. A c u t e spr. i~ B'pneum. bilat., softw a l l e d C.s . . . . . x-', mos. B ' p n e u m . bilat, w i t h some fibr. _,2 mos. Bilat. chr) clis. 2 ]arge C.s in L U Z . S o m e s o f t shad. 4 raGS. Soft dis. w i t h m e d . size C.s., w i t h u p r . h a l v e s . , t I raGS. H a r d shadows w i t h bilat. small C.s. .. 8 raGS. Soft shad. w i t h G~R. u p r . half. G o o d L A P -9 mos. Soft shad 9 R M Z with s m a l l C . L. p y o - p n e u m o . 14 mos. Soft shad. & small C.s. all zones .. . . i8 mos. M i x e d shad. u p r . halves, with C.s . . . . . 2 mos. M i x e d shad. u p r with small C.s.
N.C . . . . .
41, mos.
N.C.
S l . i m p . b o t h sides 589 mos.
N9
Impr...
4 mos.
Contl. i m p r .
S1. i m p r .
4 mos.
N.C.
N.C.
..
4 mos.
N9
det.
..
4 mos.
N.C 9
4 mos.
Det.
SI. det. Imp.
.. ..
zones ..
3 mos.
N.C.
M i x e d shad. m a i n l y L. upr. tmlf (large C.s.P.)
6 wks.
Soft dis., R M Z , h a r d e r L U Z . C.s. ,~ .9 P n e u m . dis. u p r . halves. C.s . . 9 9 . . . M i x e d shad. u p r . zones. C.s . . . . . . .
99
Result
4 mos.
Def. i m p . Loss o f C.s.
9 9
4
SI. i m p .
9.
5 mos.
Def. imp. minute
I mos.
N.C.
9.
4 mos.
Imp.
3 mos.
SI. i m p .
9 9
4
mos.
Def. imp.
3 mos.
Det.
9 9
4
mos.
N.C.
r a n g e , r e d u c t i o n in s p u t u m ; loss o f d e p r e s s i o n , g o o d a p p e t i t e a n d f r e e d o m fi'om a b d o m i n a l s y m p t o m s . T i l e c a v i t i e s in tim left l u n g b e came much smaller, but there was a slight s p r e a d to t h e r i g h t b a s e w h i c h l a t e r c l e a r e d 9 A successful r i g h t t h o r a c o p l a s t y b e c a m e possible. (3) T u b e r c u l o u s p e r i t o n i t i s (I case). T h i s
,o
..
mos.
Def. i m p , Loss o f G.s.
C.s
girl (at Grove Park)had acute appendicitis a n d a t o p e r a t i o n t h e o r g a n w a s f o u n d to b e grossly tuberculous 9 A P.P. induced later precipitated peritonitis and she became f c b r i l e , t o x i c a n d g e n e r a l l y ill. T . B . I u n doubtedly improved the abdominal cond i t i o n a n d r e d u c c d ascites a n d t h e P . P . w a s a b l e to b e c o n t i n u e d .
October 1951
T U B E R C LE
(4) Endobronchitis (3 cases proved at bronchoscopy). O f these, -2 were markedly improved by T.B.I, with contraction of accompanying tension cavities. Both showed severe bronchial disease (redness and granulations). Toxic and Side-effects
(I) Urinary changes. Albuminuria without other signs of renal dysfunction was the commonest complication (IO cases). It varied from a transient and slight haze to marked albuminuria which persisted after the end of the course for as long as two months (3 cases). It would seem that if the sign appears early in the course there is perhaps a 5 ~ per cent chance of it disappearing though treatment is continued, but it is probably unwise to persist with treatment if there is any slight increase in the amount of albumifi or it is more than when first detected. (2) Liver dysfunction. Various tests were used, in some only an estimation of serum proteins and albumin globulin ratio, in others t h e Takata-Ara test. In one patient there was a slight fall in serum proteins and in 4 (out of 8 in which the test was done) a slight alteration of the Takata-Ara. At King George V Sanatorium, following the end of the trial a filrther series of cases, given doses up to .2oo mg. a day was tested with thymol turbidity, cephalin cholesterOl and scarletred tests and no positive changes were found. (3) Blood changes. 3 patients developed secondary hypochronfic anaemia which responded to treatment, but as iron was administered prophylactically in a number of cases, this figure does not represent the actual risk. The white cells were not affected in any case. (4) Abdominal symptoms. 8 patients showed mild symptoms varying from anorexia to mild diarrhoea and vomiting. (5) Other complications. 4 cases complained of 'tightness of the chest' with or without dyspnoea and dryingup of secretions. T h i s s y m p t o m disappeared on stopping the drug, which could then be re-started at a lower dosage. In 3 patients who developed
221
a l b u m i n u r i a - that this might be of allergic origin was suggested by other s y m p t o m s - a pyrexial onset with malaise and headache and the development of a rash (rather like a confluent erythema m u l t i f o r m e ) - which responded to antihistamines. With the exception of slight albuminuria, which may prove to be transient, it may be said that toxic effects appearing when dosage is still low should probably be regarded as serious and an indication for discontinuing therapy. All accounts suggest that T.B.I is far more toxic than PAS or streptomycin, but if -2oo mg. a day be not exceeded, there does not appear to be any great danger, provided that careful control is exercised. (Incidentally for estimating liver function, it is probable that thymol turbidity, cephalin cholesterol and scarlet red tests, referred to above, are most informative.) In making a choice of cases, it would obviously be wise to rule out those with existing renal or hepatic damage or with intercurrent infections likely to throw a strain on the liver. The 9 count also should be within normal limits. Discussion
It should be stressed that the Committee was not so impressed by the German reports as to embark immediately on a controlled trial or to choose any type of case but the unfavourable one into which most of our patients fell. It was argued that it might be unfair to withhold streptomycin from even those patients who had what is now known as the 'M.R.C. type' of disease. The hurdle set up was, therefore, a difficult one to surmount. Taking into consideration the G e r m a n figures, the results of this pilot trial and, perhaps still more, the opinions of the clinicians concerned with regard to unexpected improvements, it may be said that T.B.I has some tuberculostatic activity. But in view of its acknowledged limitations with regard to haematogenous tuberculosis, the slowness (and probably limited effectiveness) in obtaining results as compared to streptomycin and its increased toxicity as compared
222
T U BERC L E
October 1951
[8] Sturm, A. (1949) Dent. Med. ll'chnschr., x x m , 726, to both streptomycin and PAS, there must 19l Klee, P. (195 o) Beitr. I;lbt. Tuberk. ell, 625. be some doubt as to whether it should be [to] Wilde, W., a n d Ruck, K. H. 0 9 5 0 ) Med. Monatsschr., IV, 601. selected at all in planning the treatment of [! I] Arold, C. (x948) Dent. Gesundh.-Wesen, vb ~ tuberculosis. It may on occasions be useful lI2] Arold, C. (I949) .~schr. F. Lar.)'ngologic, Rhbzologie, Otologffk 1o5. if it can be shown to have an effect com[13] D o m a g k , G., anti others (195o) Chemodlerapie der parable to that of PAS in preventing the Tuberkulose mit den Tbiosemikarbazonen, Stuttgart. development of streptomycin resistance, and [I4] D u n n , G. (t95o) Pharm. 07., CLXI~.b 169. this the trial now being undertaken by the [t5] Bavin, E. M., Rees, R. J. W., et al. (195o) 07. Pharmao'. Pharmacol., n, 76.t. N.W. Tuberculosis Society should determine. [16] Hogarth, E., and Martin, A. R. 0 9 5 ~ ) Brit. 07. On the other hand, this pilot trial seems Pharmacol., v, x88. to show that with doses probably not more [17] Livingstone, R., and Street, E. W. (1951) Tubercle, XXXII, 8. than 2oo nag. a day, the toxic effects of [18] Moeschlin, S., a n d Demiral, B. 0 9 5 o) Schwelz. M~d. II'schr., LXXX, 373" T.B.I are not serious if a carefitl routine is [xg] Sim,nons, G., Ilobsou, I.. B., et al. (095o) Amer. Rev. carried out. It has the advantage of oral Tuberc., t.xH, 128, administration and its optimum effect appears to be on mucosal lesions. In such cases, whenever there is a desire to avoid any Tuberculin Testing and Vaccination hazard of drug resistance to streptomycin, it The following table applies to countries may be of value. assisted by the International Tuberculosis Campaign and gives the numbers of individuals Summary A report is given of a small pilot trial tested, the numbers of reactors and the m~mbers vaccinated, up to December I, 195o. The carried out at several institutions. P-acetyl- tttberculin testing was not performed according anainobenzaldehyde thiosemicarbazone to a standardized technique. The table is taken (T.B. i ]698 ) was given for varying periods to from H. J. Ustvedt's article on Mass kraccinaa total of 45 patients. The type of case tion Campaigns with BCG in the Courrier of t selected was usually not such as to favour March I95 I. beneficial effects from an antibiotic, but the Counlry Tested Positive Vaccinated results seemed to support the claim that T.B.I has some bacteriostatic effect. A short Austria . . . . 7.t8,I64 49,I3 t 513,~41 review of the current position of the drug is Czechoslovakia .. 3,421,876 x,o36,656 -'2,o88,-t46 Finland . . . . 75o,ooo -362-,ooo also given. Greece . . . . 1,458,2o6 38o,8o8 !,ooo,329 The following were the senior clinicians Hungary . . . . 3,o95,146 1,9o3,402 1,oSx,39x . . . . . . 5o,-to~ 14,9o2 28,636 concerned: Dr R. Cunningham (Poole Italy Malta . . . . 54,968 9,962 . 38,77 o Sanatorium); Dr J, V. Hurford (King Poland . . . . 5,514,o36 2,512,321 2,535,026 . . . . .2,955,272 I,olx,558 1,533,9o8 George V Sanatorium); Dr G. S. Erwin Jugoslavia Arab Refugees .: 21 i,3o-3 25,751 148,t37 (Liverpool Sanatorium); Dr M. M. Nagley l'gypt . . . . 89~,974 278,767 2.1o,588 ..... 342,o9 o 87,967 199,.t37 (Grove Park Hospital); Dr W. L. Yell Israel Lebanon . . . . 43,463 5,35-t 28,3x t (Broomfield Hospital). Syria . . . . 265,o85 6o,21o ~ ~5,582 References
[x] Domagk, G., Behnlach, R., Mietz_sch, F., and Schmidt, II. (1946) Naturwissev Schaftepz, x, 315 . [2] Domagk, G. (195o) Amer. Bey. Tuberc., LXl, 8. 13] IIogarth, I".., Martin, A. R., Storey, N. E., Young, E. It. P. 09t9) Brit. 07. Pharmacol., IV, 248. [4] Martin, A. F,., and Stewart, G. T. (195o) Brit. 07. of Exp. Path., XXXl, 2, ~89. [5l Spain, D. M., Childress, W. G., and Fishler, J. S. (195o) Amer. Rev. Tuberc., LXXl, ~4-t[6] Mertcns, A., and Bunge, F,. 095 ~ ) Amer. Rev. Tubere., L X I , 2 0 . [7] Hilashaw, H. Corwin, and McDermott, W. (~95 o) Rep. to Amer. "Frudean Soc., Amer. Rev. Tubere., LX~, ~45"
Algeria Morocco Tangiers Tunisia Ceylon India . . . Pakistan
Ecuador Mexico
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . .
Danish Red Cross Germany, Swedisl~ Red Cross ..
1,186,637 352,o3t 1,572,245 565,145 21 ,o89 . 8,771 421,792 x 19,322 32,639 .20,827 2,538,ol I I,.222,oI 4 478,o7x 2o4,928 258,t64 88,315 x'~9,6oo 34,976
49o,9o8 699,64 ~ 7,-}93 197,774 5,641 865,968 t.t2,.2ox 132,o7 o 64,512
b658,868
54o,7x5
51 x,663
3,678,737
1,233,323
x,367,999
Germany,
G r a n d t o t a l as at December t, x95 o 31,778,o57 ti,795,166 I.t,399,645
217
Thiosemicarbazone in Chemotherapy of Tuberculosis Report of Pilot Trial organized by the Research Committee of the British TuberculosisAssociation This paper attempts a review of the present status of thiosemicarbazone therapy in tuberculosis and makes a report on a small pilot trial carried out in this country u n d e r the auspices of the Research Committee oF tile British Tuberculosis Association. The pioneer work on thioscmicarbazone was performed by Domagk [t] and his colleagues in Germany. He reported in i946 that of a number of thiosemicarbazones p-acetylaminobenzaldehyde thioscmicarbazone (T.B.I [698 ) was tile most active against the M. tuberculosis in vitro and in experimental animals. It appeared to have a different mode of.action from streptomycin and PAS and not to be antagonized by para-alnino9benzoic acid. In vitro and in guinea-pig infection, T.B.I was weight for weight more efficacious than PAS, even in a dose Ioo times smaller than the latter. Domagk later reported that it inhibits growth on culture m e d i u m containing p-aminobenzoic acid at three times as high a dilution as even streptomycin [2]. Since I946. other workers have examined the thiosemicarbazones and it would seem that T.B.I is not as effective (at any rate in tuberculous infection of mice) as p-ethylsulphonylbenzaldehyde thiosemicarbazone (T.B.III in Germany) [3, 4] which in this content was more highly active than PAS and even superior to streptomycin in the early stages of disease. On the other hand, Spain, Childress and Fishler [5] found that T.B.I (Tibione) also could be favourably compared with streptomycin in treating tuberculosis in guinea-pigs. At any rate, all the clinical trials so far have been concerned with tile use of T.B.I. In October I949 Mertens and Bunge reported that 'far more than IO,OOO patients had been treated and over 6o clinical papers published or pending in Germany' [6]. The favourable results reported were placed in focus by Hinshaw and McDermott [7] who in I95O on behalf of the National Tuberculosis Association of America visited 8 insti-
tutions in Germany. There was an absence of controls and often the periods of observation were short, the use o f paper films sometimes made assessment difficult and in any case evaluation of this type of therapy against tuberculosis in a general population recovering from a period of malnutrition was bound to be difficult. The popularity of T.B.I in Germany was probably influenced in its early stages by its low cost of production compared with high price (in dollars) of streptomycin and PAS. All the reports imply that T.B.I, like other antibiotics, in pulmonary tuberculosis affects favourably the more labile lesions. Sturm [8] for instance reports on x 17 cases so trcated and Klee [9] on 200 cases treated for thirty months. As well as being slower in action than streptomycin, T.B.I is also less certain, however, even in such favourable lesions. Extensive caseation and chronic disease respond little. Acute miliary tuberculosis and tuberculous meningitis are not influenced and this may be due to the slower onset of the thiosemicarbazone effect (Mertens and ,Bunge [6]). Tile alleged favourable effect of T.B. I on mucosal tuberculosis may account for changes which have bccn reported in softwalled and distension cavities. Mertens and Bunge emphasized that recession of a cavity may not be permanent if T.B.I is stopped too soon and that it should be continucd for at least six months. In addition to .or instead of peroral thiosemicarbazone, the drug has been instilled into cavities undergoing drainage (Wilde 'and Ruck [IO]) and good results reported. It has been estimated that T.B.x. will influence favourably 80 per cent or more of cases of tuberculous laryngitis (Arold [ I I, I ~]) and many cases of ulceration of the tongue. Tuberculosis of the intestines and of tile bladder and ureter and urethra will also respond. Papers read at the 55th Congress of Internal Medicine held at Wiesbaden in
218
T U B ERC L E
I949 emphasize the place given to T.B.I by the Germans in these various forms of tuberculosis. The beautifully produced monograph published in German in I95O under the editorship of G. Domagk brings together the views of leading workers in his country. In this country, published work has been sparse. Dunn [i4] , Bavin et al. [i5] , Hogarth and Martin [I6] have all reviewed the pharmacological aspects. The only clinical paper has been one by Livingstone and Street [I7] reporting on a small series Of uncontrolled cases treated by the drug. It is certain, however, that a number of clinicians have been using it, perhaps sometimes rather haphazardly. Moesehlin and Demiral [~8] concluded on experimental evidence that the activity of T.B.I was somewhat less than that of PAS, that combining streptomycin and the former drug was no improvement on the use of streptomycin alone and that streptomycin and PAS was undoubtedly the best combination. Dosage: In contradistinction to laboratory animals, in which tlfiosemicarbazones are relatively poorly absorbed, T.B.I is not tolerated well by human beings and after a preliminary period in which higher doses were used, most clinicians now do not exceed .ooo rag. a day. A dose of 2 rag. per kilo body-weight has been recommended, but it is probable that this can be exceeded in many cases without incurring side-effects. In any event, the maximum dose should be reached by gradual increases from a preliminary 5 ~ mg. a day.
Complications T h a t T.B.I may have toxic effects was reported by the German workers. Simmons and his colleagues [I9] adnfinistered the drug (Myvizone) in large doses (up to a maximum of 8oo nag. a day) to I6 patients, most of whom had untoward symptoms, including disturbed liver fimction and it was, however, interesting that the side-effects were not more severe or permanent. The
October 1951
toxic phenomena reported by the Germans largely date back to a period when the preparation was given in a combination with sulphathiazole (Eleudron) or when the doses were larger than are usual now. Domagk [I] detailed the following: (I) Gastro-intestinal complications - disturbed appetite and nausea. Vomiting occurring later in the course should lead to discontinuation of T.B.x. (2) Allergic phenomena - mild conjunctival irritation and possibly exanthenaata of various types including severe lmemorrhagic forms. (3) Haematopoietic changes-occasionally on agranulocytosis (hIertens and Bunge dcscribe an allergic form with eosinophilia) which may be ushered in with an increase in fever. Haemolyric anaemia may occur. (4) Renal d a m a g e - aibunainuria, usually disappears spontaneously or when drug is stopped. (5) Liver d a m a g e - with jaundice, strong urobilinogen reaction, positive Takata-Ara test and other signs (Mertens and Bunge throw doubt on hepatotoxicity as being due to T.B.I in present doses). (6) Eneephalopathy - increased intracranial pressure, with headache. Probably unlikely with present doses. The early reports of such toxic effects gave the impression that thiosemicarbazone was an unusually poisonous substance. Since, however, it had received such praise from German workers and was becoming available in this country, the B.T.A. Research Committee decided to attempt a pilot trial as a prelude to it possible more scientific investigation on a wider scale. The following account is of the foriner. It should be stressed that when it was envisaged tim Committee was by no means convinced by the German figures but more impressed by the reported toxic effects, so the pilot trial was to a great extent designed to confirm the safety of the so-called 'safe' doses, whilst using individuals with a type of
October 1951
disease for which, streptomycin immediately indicated.
T U BERC L E
was not
Pilot Trial 9For the reason given in the previous paragraph, the type of case prescribed had chronic, bilateral fibrocaseous disease with some radiological shadows that might be judged likely to response to an antibiotic. This definition was observed in most instances though (especially in the Grove Park patients) T.B.z was sometimes given for specific indications, e.g. laryngitis or an isolated distension cavity or abdominal involvement. In all, 45 cases were reviewed, the results being assessed by the individual clinicians and summarized centrally from their reports. T h e following description has been deliberately kept brief in order not to appear to overstress a trial carried out on, for the most part, unfavourable cases over what might be claimed to be an inadequate period. Five institutions participated-Broomfield Hospital, Liverpool Sanatorium, Poole Sanatorium, King George V Sanatorium and" Grove Park Hospital. The drug (Conteben) was given orally, at first in graduated doses fi'om 25 to 5 ~ mg. a day up to an effective dose of fi'om 2 nag. per kilo body-weight to 0.5o mg. a day. A course of four months had been prescribed and more than half the cases finished that period or longer (three or five months, o for six months), but 9 had only three months and some as little as two months, the course having been interrupted because of complications or general deterioration or because 'collapse therapy became practicable and desirable. A very small uumber of patients had been observed for less than two months and many for much longer (2x for four months or more); changes in that time were taken into account in assessing results of treatment. X-ray Changes The table gives results in 25 patients who had T.B.I, primarily for pulmonary lesions, for at least four months. In I0. there was
219
x-ray improvement which might be attributed to the drug and the most frequent effect seemed to be on cavities. There were favourable changes in others who had T.B.I for less than four months. O f 9 so treated for between three and four months, four showed significant improvement. General Effects Though a proportion of patients showed improvement in general well-being, appetite and weight, this could not ahvays be correlated with radiological change and was lcss marked than that which many observers have found to accompany administration of PAS. The same can be said with regard to changc in tile E.S.R. Neither was there any constant effect on temperature. O f the 25 cases treated for four months or more, I was sputum negative throughout and of the remainder, there were only 5 conversions to negative. Effects on Complications (z) Laryngeal tuberculosis (9 cases). 4 showed marked and 3 moderate improvement. The former were no doubt affected by administratiou of T.B.I, but in the latter this cannot be deduced, except perhaps in one patient Who had an 'allergic' reaction (see below) and in whom in the eleven days before the drug was discontinued had shown a definite improvement with regard to the laryngeal condition. (2) Tuberculous enteritis (2 cases). In one patient the condition was terminal and no conclusions can be drawn as he had gross disease elsewhere and died. The other (at Broomfield Hospital) was a man of 33, who had had pulmonary tuberculosis for approxinmtely two years. The ltmgs showed mainly Icft-sided disease with cavities in the upper half, one of them moderately large. His general condition was poor, with evening pyrexia (99 ~) and continual complaints of dyspepsia and bouts of diarrhoea and general dispiritedness. Conteben had a marked effect on all general symptoms: fall of temperature to normal
220
T U BERC LE TAB
October 1951
LE
Case
Age
Disease
Obs.
Change dur. obs.
Dur. of T.B. I
I 2 3
24 34 35
8 mos. 6 mos.
N.C . . . . . S1. l a r g e r .-
4 mos. 5 mos.
C. s m a l l e r G. s m a l l e r
I2 mos.
G. imp. in R U Z
4 mos.
G. s m a l l e r
4
25
Tens. C. L U L . . . . . do . . . . . "Fens. C. R U L . , Chr. dis. RUZ & RhlZ... Chr. dis. R. h m g 2 large C. L U Z . . . . .
I2 mos.
Tendency to spread N.C . . . . .
6mos. 5 mos.
G. imp., one much smaller C. s m a l l e r
Spr. L. l u n g
..
4 mos.
C. almost gone
Resistant t o S / M Resistant t o S / M
4 mos. 4 mos.
N.C. N.C.
Little eh.
4 mos.
N 9149
5 6
3x 31
7
26
98 9
33 3I
io
44
II
39
x2
35
13
27
14
2~
15
29
16
38
x7
26
x8
19
I8
33
20
5~
2x
44
22
43
2 Tens. C. L U Z . . . . 7 raGS. S c a t t e r e d dis. L . h m g . C. b l o w n u p L U L . . 3 mos. Bilat. exud. dis. w i t h recent C.s .. 8 4 days T ' p l a s t y R. A c u t e spr. i~ B'pneum. bilat., softw a l l e d C.s . . . . . x-', mos. B ' p n e u m . bilat, w i t h some fibr. _,2 mos. Bilat. chr) clis. 2 ]arge C.s in L U Z . S o m e s o f t shad. 4 raGS. Soft dis. w i t h m e d . size C.s., w i t h u p r . h a l v e s . , t I raGS. H a r d shadows w i t h bilat. small C.s. .. 8 raGS. Soft shad. w i t h G~R. u p r . half. G o o d L A P -9 mos. Soft shad 9 R M Z with s m a l l C . L. p y o - p n e u m o . 14 mos. Soft shad. & small C.s. all zones .. . . i8 mos. M i x e d shad. u p r . halves, with C.s . . . . . 2 mos. M i x e d shad. u p r with small C.s.
N.C . . . . .
41, mos.
N.C.
S l . i m p . b o t h sides 589 mos.
N9
Impr...
4 mos.
Contl. i m p r .
S1. i m p r .
4 mos.
N.C.
N.C.
..
4 mos.
N9
det.
..
4 mos.
N.C 9
4 mos.
Det.
SI. det. Imp.
.. ..
zones ..
3 mos.
N.C.
M i x e d shad. m a i n l y L. upr. tmlf (large C.s.P.)
6 wks.
Soft dis., R M Z , h a r d e r L U Z . C.s. ,~ .9 P n e u m . dis. u p r . halves. C.s . . 9 9 . . . M i x e d shad. u p r . zones. C.s . . . . . . .
99
Result
4 mos.
Def. i m p . Loss o f C.s.
9 9
4
SI. i m p .
9.
5 mos.
Def. imp. minute
I mos.
N.C.
9.
4 mos.
Imp.
3 mos.
SI. i m p .
9 9
4
mos.
Def. imp.
3 mos.
Det.
9 9
4
mos.
N.C.
r a n g e , r e d u c t i o n in s p u t u m ; loss o f d e p r e s s i o n , g o o d a p p e t i t e a n d f r e e d o m fi'om a b d o m i n a l s y m p t o m s . T i l e c a v i t i e s in tim left l u n g b e came much smaller, but there was a slight s p r e a d to t h e r i g h t b a s e w h i c h l a t e r c l e a r e d 9 A successful r i g h t t h o r a c o p l a s t y b e c a m e possible. (3) T u b e r c u l o u s p e r i t o n i t i s (I case). T h i s
,o
..
mos.
Def. i m p , Loss o f G.s.
C.s
girl (at Grove Park)had acute appendicitis a n d a t o p e r a t i o n t h e o r g a n w a s f o u n d to b e grossly tuberculous 9 A P.P. induced later precipitated peritonitis and she became f c b r i l e , t o x i c a n d g e n e r a l l y ill. T . B . I u n doubtedly improved the abdominal cond i t i o n a n d r e d u c c d ascites a n d t h e P . P . w a s a b l e to b e c o n t i n u e d .
October 1951
T U B E R C LE
(4) Endobronchitis (3 cases proved at bronchoscopy). O f these, -2 were markedly improved by T.B.I, with contraction of accompanying tension cavities. Both showed severe bronchial disease (redness and granulations). Toxic and Side-effects
(I) Urinary changes. Albuminuria without other signs of renal dysfunction was the commonest complication (IO cases). It varied from a transient and slight haze to marked albuminuria which persisted after the end of the course for as long as two months (3 cases). It would seem that if the sign appears early in the course there is perhaps a 5 ~ per cent chance of it disappearing though treatment is continued, but it is probably unwise to persist with treatment if there is any slight increase in the amount of albumifi or it is more than when first detected. (2) Liver dysfunction. Various tests were used, in some only an estimation of serum proteins and albumin globulin ratio, in others t h e Takata-Ara test. In one patient there was a slight fall in serum proteins and in 4 (out of 8 in which the test was done) a slight alteration of the Takata-Ara. At King George V Sanatorium, following the end of the trial a filrther series of cases, given doses up to .2oo mg. a day was tested with thymol turbidity, cephalin cholesterOl and scarletred tests and no positive changes were found. (3) Blood changes. 3 patients developed secondary hypochronfic anaemia which responded to treatment, but as iron was administered prophylactically in a number of cases, this figure does not represent the actual risk. The white cells were not affected in any case. (4) Abdominal symptoms. 8 patients showed mild symptoms varying from anorexia to mild diarrhoea and vomiting. (5) Other complications. 4 cases complained of 'tightness of the chest' with or without dyspnoea and dryingup of secretions. T h i s s y m p t o m disappeared on stopping the drug, which could then be re-started at a lower dosage. In 3 patients who developed
221
a l b u m i n u r i a - that this might be of allergic origin was suggested by other s y m p t o m s - a pyrexial onset with malaise and headache and the development of a rash (rather like a confluent erythema m u l t i f o r m e ) - which responded to antihistamines. With the exception of slight albuminuria, which may prove to be transient, it may be said that toxic effects appearing when dosage is still low should probably be regarded as serious and an indication for discontinuing therapy. All accounts suggest that T.B.I is far more toxic than PAS or streptomycin, but if -2oo mg. a day be not exceeded, there does not appear to be any great danger, provided that careful control is exercised. (Incidentally for estimating liver function, it is probable that thymol turbidity, cephalin cholesterol and scarlet red tests, referred to above, are most informative.) In making a choice of cases, it would obviously be wise to rule out those with existing renal or hepatic damage or with intercurrent infections likely to throw a strain on the liver. The 9 count also should be within normal limits. Discussion
It should be stressed that the Committee was not so impressed by the German reports as to embark immediately on a controlled trial or to choose any type of case but the unfavourable one into which most of our patients fell. It was argued that it might be unfair to withhold streptomycin from even those patients who had what is now known as the 'M.R.C. type' of disease. The hurdle set up was, therefore, a difficult one to surmount. Taking into consideration the G e r m a n figures, the results of this pilot trial and, perhaps still more, the opinions of the clinicians concerned with regard to unexpected improvements, it may be said that T.B.I has some tuberculostatic activity. But in view of its acknowledged limitations with regard to haematogenous tuberculosis, the slowness (and probably limited effectiveness) in obtaining results as compared to streptomycin and its increased toxicity as compared
222
T U BERC L E
October 1951
[8] Sturm, A. (1949) Dent. Med. ll'chnschr., x x m , 726, to both streptomycin and PAS, there must 19l Klee, P. (195 o) Beitr. I;lbt. Tuberk. ell, 625. be some doubt as to whether it should be [to] Wilde, W., a n d Ruck, K. H. 0 9 5 0 ) Med. Monatsschr., IV, 601. selected at all in planning the treatment of [! I] Arold, C. (x948) Dent. Gesundh.-Wesen, vb ~ tuberculosis. It may on occasions be useful lI2] Arold, C. (I949) .~schr. F. Lar.)'ngologic, Rhbzologie, Otologffk 1o5. if it can be shown to have an effect com[13] D o m a g k , G., anti others (195o) Chemodlerapie der parable to that of PAS in preventing the Tuberkulose mit den Tbiosemikarbazonen, Stuttgart. development of streptomycin resistance, and [I4] D u n n , G. (t95o) Pharm. 07., CLXI~.b 169. this the trial now being undertaken by the [t5] Bavin, E. M., Rees, R. J. W., et al. (195o) 07. Pharmao'. Pharmacol., n, 76.t. N.W. Tuberculosis Society should determine. [16] Hogarth, E., and Martin, A. R. 0 9 5 ~ ) Brit. 07. On the other hand, this pilot trial seems Pharmacol., v, x88. to show that with doses probably not more [17] Livingstone, R., and Street, E. W. (1951) Tubercle, XXXII, 8. than 2oo nag. a day, the toxic effects of [18] Moeschlin, S., a n d Demiral, B. 0 9 5 o) Schwelz. M~d. II'schr., LXXX, 373" T.B.I are not serious if a carefitl routine is [xg] Sim,nons, G., Ilobsou, I.. B., et al. (095o) Amer. Rev. carried out. It has the advantage of oral Tuberc., t.xH, 128, administration and its optimum effect appears to be on mucosal lesions. In such cases, whenever there is a desire to avoid any Tuberculin Testing and Vaccination hazard of drug resistance to streptomycin, it The following table applies to countries may be of value. assisted by the International Tuberculosis Campaign and gives the numbers of individuals Summary A report is given of a small pilot trial tested, the numbers of reactors and the m~mbers vaccinated, up to December I, 195o. The carried out at several institutions. P-acetyl- tttberculin testing was not performed according anainobenzaldehyde thiosemicarbazone to a standardized technique. The table is taken (T.B. i ]698 ) was given for varying periods to from H. J. Ustvedt's article on Mass kraccinaa total of 45 patients. The type of case tion Campaigns with BCG in the Courrier of t selected was usually not such as to favour March I95 I. beneficial effects from an antibiotic, but the Counlry Tested Positive Vaccinated results seemed to support the claim that T.B.I has some bacteriostatic effect. A short Austria . . . . 7.t8,I64 49,I3 t 513,~41 review of the current position of the drug is Czechoslovakia .. 3,421,876 x,o36,656 -'2,o88,-t46 Finland . . . . 75o,ooo -362-,ooo also given. Greece . . . . 1,458,2o6 38o,8o8 !,ooo,329 The following were the senior clinicians Hungary . . . . 3,o95,146 1,9o3,402 1,oSx,39x . . . . . . 5o,-to~ 14,9o2 28,636 concerned: Dr R. Cunningham (Poole Italy Malta . . . . 54,968 9,962 . 38,77 o Sanatorium); Dr J, V. Hurford (King Poland . . . . 5,514,o36 2,512,321 2,535,026 . . . . .2,955,272 I,olx,558 1,533,9o8 George V Sanatorium); Dr G. S. Erwin Jugoslavia Arab Refugees .: 21 i,3o-3 25,751 148,t37 (Liverpool Sanatorium); Dr M. M. Nagley l'gypt . . . . 89~,974 278,767 2.1o,588 ..... 342,o9 o 87,967 199,.t37 (Grove Park Hospital); Dr W. L. Yell Israel Lebanon . . . . 43,463 5,35-t 28,3x t (Broomfield Hospital). Syria . . . . 265,o85 6o,21o ~ ~5,582 References
[x] Domagk, G., Behnlach, R., Mietz_sch, F., and Schmidt, II. (1946) Naturwissev Schaftepz, x, 315 . [2] Domagk, G. (195o) Amer. Bey. Tuberc., LXl, 8. 13] IIogarth, I".., Martin, A. R., Storey, N. E., Young, E. It. P. 09t9) Brit. 07. Pharmacol., IV, 248. [4] Martin, A. F,., and Stewart, G. T. (195o) Brit. 07. of Exp. Path., XXXl, 2, ~89. [5l Spain, D. M., Childress, W. G., and Fishler, J. S. (195o) Amer. Rev. Tuberc., LXXl, ~4-t[6] Mertcns, A., and Bunge, F,. 095 ~ ) Amer. Rev. Tubere., L X I , 2 0 . [7] Hilashaw, H. Corwin, and McDermott, W. (~95 o) Rep. to Amer. "Frudean Soc., Amer. Rev. Tubere., LX~, ~45"
Algeria Morocco Tangiers Tunisia Ceylon India . . . Pakistan
Ecuador Mexico
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . .
Danish Red Cross Germany, Swedisl~ Red Cross ..
1,186,637 352,o3t 1,572,245 565,145 21 ,o89 . 8,771 421,792 x 19,322 32,639 .20,827 2,538,ol I I,.222,oI 4 478,o7x 2o4,928 258,t64 88,315 x'~9,6oo 34,976
49o,9o8 699,64 ~ 7,-}93 197,774 5,641 865,968 t.t2,.2ox 132,o7 o 64,512
b658,868
54o,7x5
51 x,663
3,678,737
1,233,323
x,367,999
Germany,
G r a n d t o t a l as at December t, x95 o 31,778,o57 ti,795,166 I.t,399,645