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Thiosemicarbazones in the treatment of pulmonary tuberculosis
TUBERCLE
A compromise scheme might be based on the following points: (I) Future planning should concentrate on areas with a proved high incidence of tuberculosis. (2) In these areas, surveys of organized groups should be annual, or bi-annual, and be followed by extensive open sessions for the public. (3) In areas of a lesser incidence of tuberculosis and where mass surveys of
January 1951
organized groups have already taken place in the past, follow-up examinations should be considerably curtailed and replaced by open public sessions at intervals determined by the number of tuberculous found. (4) Priority for the under 35 s should be asked for in all follow-up surveys, although it is realized that arrangements to this effect are not always easy to make.
Thiosemicarbazones in the Treatment of Pulmonary Tuberculosis By ROBERT LIVINGSTONE
Physician Superintendent and EDMUND W . STREET
Senior Assistant Medical Officer, Lenham Sanatorium Of recent years considerable interest has been aroused, particularly in Germany, by theuseofthiosemicarbazones in the treatment of pulmonary and other forms of tuberculosis. Of the series of thiosemicarbazones investigated by Domagh and his colleagues [I], para-acetylamino benzaldehyde thiosemicarbazone (TBI) has given the most encouraging results, hz vitro experiments by Drain and others [2] using a modified Dubos' medium showed that the drug possessed an inhibitory effect on M. tubemtlosis, strain H37RV , in a concelatration of the order of o.o5-o.i mg. per I OO rot. medium. This activity appears to be unaffected by the presence of para-aminobenzoic acid [3]. Experiments by Domagh [4] and Levaditi [5] on animals with induced tuberculosis have shown TBI to have a definite suppressive action. At present extensive use of the drug has been confined almost exclusively to Germany and the results have been considered in detail by Hinshaw and McDermott [6] who consider that the results justify controlled trials. In an evaluation of the results in 64 patients suffering from acute forms of pulmonary tuberculosis these writers found
decided improvement in 59 per cent of cases and partial improvement in x9 per cent, while in 2 2 p e r cent of cases there was no change. In chronic forms of the disease they report that of 57 patients marked improvement was observed in 5 per cent, partial improvement in 28 per cent, while in 67 per cent of cases there was no change. In another i36 patients there was improvement in recent or progressive lesions in 19 cases (I 4 per cent), shrinkage of cavities in 7 (5 per cent), sputum conversion in I2 (8. 9 per cent), reduction in temperature in 28 (2o. 5 per cent), iinprovement in the sedimentation rate in 27 (I9.8 per cent), and collapse therapy made possible in 7 cases (5 per cent). In a further 94 cases evaluated they report striking convincing improvement in 29 cases (3o.8 per cent), and probable evidence of good result in I8 cases (I9 per cent). Wifll regard to toxic effects Hinshaw and McDermott report that anorexia, malaise, and occasional vomiting were fairly common; these symptoms appeared to be related to the amount of drug given and subsided when the dose was reduced. An unknown percentage of patients developed mild anaemia
January 1951
TUBERCLE
Dosage and mention is made of a few cases with haemolytic reactioris due presumably to All patients, commenced with one 5 ~ ing. excessive dosage. Agranulocytosis was re- tablet daily for three days, two 5 ~ mg. ported in 8 cases among 2,ooo patients but tablets daily for the next three days, and several of these were receiving aminopyrine fQur 5 ~ nag. tablets daily thereafter. In Case at the time agranulocytosis developed. 6 nausea permitted only three tablets (i5o Several cases of mild albuminuria were mg.) to be taken daily, while in Cases 7, 8, 9, reported but in no case was definite renal IO and I I the daily dose was raised to six damage apparent, Skin rashes appeared to tablets (300 mg.) after three months without be fairly common but rarely severe. In a ill-effect. The tablets were given either one considerable number of cases jaundice "or two at a time after meals, and treatment occurred and although there was consider- was in most cases continuous for up to five able confusion as to its origin, in many months. instances it could be attributed to the use of During t h e investigation sputum and TBI. The jaundice appeared to be d u e to x:ray examinations were done at monthly fatty infiltration and in the opinion of most intervals. A complete blood count was done observers the change was reversible. .monthly and a differential white count at ~;eekly intervals. Also at weekly intervals an estimation was made of the serum proteins, Material In view of these encouraging results T B I serum alkaline phosphatase and blood urea. was tried out on I2 patients. The actual The colloidal gold reaction was also done drug used is marketed under the name weekly. The blood chemistry will be the 'Thioparamizone' and is available in tablets subject of a future communication. of 5 ~ mg. O f the z2 patients, 7 were male Case Reports and 5 female. 3 patients suffered from relaCase I . M r s F. C., aged 33. Admitted on tively recent disease (Cases 2, 5 and 6), 7 12.ix.49 With a h!story pulmonary tubercufrom more chronic disease (Cases I, 4, 8, 9, losis extending over twoofyears. X-ray showed xo, z z and z2), and 2 were suffering.from widespread fibrocaseous disease throughout the endobronchial tuberculosis (Cases 3 and 7). whole of the left lung, with infiltration and Apart from Case z where treatment was cavitation in the upper zone of the right lung. started one month after admission, all cases There was also present 'a pneumopentor~eum which had been induced thi'ee months previously. had previously been under observation for Sputum T B + , E.S.K. 92[2oo (Westergren), at least three months, and had had various evening temperature IOO~ F., pulse I t2, x~'eight other forms of active and chemotherapeutic 96 lb. The patient was very thin and pale and a measures t r i e d wittkout any remarkable moderate degree of toxaemia was presen t. A success. All cases apart from Case 5 had had course of PAS 2o grammes daily was commenced three days after admission and continued for a course of PAS previously, Cases 3, 6 and 7 five and a half months. By this time the patient's had had streptomycin, Cases 7 and 8, temperature was normal, pulse 92 , sputum artificial pncumothorax, Cases I, 3, 6 and z2, T B + , E.S.R. 95/2oo (Westergren), weight pneumoperitoneum, and Case 3, postural Io9 lb. There was no appreciable radio log'ical retention. In Cases IO and I I, PAS was also change. The organism was now resistant to a given concurrently with TBI, and in Case 8 concentration of 6"4 rag. PAS per Too ml. medium.' PAS was stopped and TBx was comstreptomycin z gramme daily was given menced on ~9.4.5 o and continued for I5I days. concurrently. Case I I had a right artificial The most noticeable effect was the rapid fall in the E.S.R. which dropped from 95/200 to pneumothorax induced and maintained during the course of treatment. The pro- 52/2oo in fourteen days, having previously longed observation p e r i o d prior to com- remained at an average level of 97[2oo for six months. Thereafter the E.S.R. progressively fell mencing treatment no doubt accounts for and two months later was zo/2oo and remained the fact that none of the patients was febrile, at that level throughout the course of treatment.
I0
TUBERCLE
January 1951
At the end of five antl a half months' treatment changed. On ~3.6.5o, forty-threc days aficr tile the Sl)Utum rcmaincd "I'B-~- and there was very course of streptomycin had bccn c()mplcted and little change in the radiological picture ,,f the tbrty-t})ur days after commencing '/'Ill l)ronchohmgs. The weight had drol?pcd to m I lb., and scopy showed the tracheal ulceration to have the daily amount of sputum was unchanged. healed completely and the left main-stem bronCase 2 . - Mrs L. H., aged 23. Admitted on elms was now patent. After five and a half 5.,t.5 ~ following a small haemoptysis three months' treatment with TBI t h e sputum was months previously. The patient had been still T B + , tile E.S.R. had fallen to i3/2oo , and continuously in bed for three months before tile x-ray fihn showed re-aeration of tile left admission. X-ray showed scattered infiltration h m g which, however, contained m a n y large throughout the upper zone of the left lung; cavities; the lesion on the right side was sputum TBq-, E.S.R. 3/2oo (Westergren). The practically unchanged. During the course of general condition was fair, pulse and tempera, treatment the patient continued progressively ture were within normal limits, and there were to lose weight and at the end of the course no signs of toxicity. PAS 20 grammes daily was weighed I 15 lb., a loss of_o5 lb. given from 20.4.50 and TBI from 29.,1.5o. Case 4- - Mr S. K. L., aged 33. Admitted on PAS was discontinued after twenty-six days 27.x.5 o with a history of pulmonary tubercubecause of nausea which ceased when PAS was losis extending over six years. Before admission stopped. '/'he sputum became T B - - seventy he had been on bed rest and PAS i8-grammes days after treatment had commenced and has daily for six months and a left phrenic crusl~ remained so. After five and a half months' had been performed three months prior to treatment the x-ray picture shows very con- admission. It was considered that in view of the siderable clearing although some infiltration chronic nature of the disease further treatment persists in the left upper zone. The amount o was unlikely to be of benefit. On admission the sputum has been reduced from half an ounce sputum was T B + , E.S.R. 24/2oo (Westergren), daily to a trace and the patient has gained 3 lb. and the x-ray picture showed widespread fibroin weight. caseous disease throughout the whole of the left C a s e " 3 . - Mrs J. E,., aged 24. Admitted on hmg w i t h more recent progressive exudative i I.Io.49 with a history of pulmonary tubercu- disease of the right upper zone. "/'he temperature losis extending over twelve months. Serial and pulse were normal and t h e weight was x-rays showed progressive parenchymal disease 154 lb. During the next three months the on the left side d u r i n g this time in spite of condition of the disease in the left lung remained continued bed rest. On admission an x-ray unchanged but the right side of the chest showed scattered exudative lesions throughout showed a progressive if slow increase in the the whole of t h e left lung and an area of fine infiltrative lesion. On sputum culture the mottling at the periphery of the .right mid-zone. organism was found to be resistant to a conThe sputum was T B + , E.S.R. 46/2oo (Wester- centration of 3.2 rag. PAS per IOO ml. medium. gren). The evening temperature was 99 ~ F. and A course of TBI was commenced on 8.5.5o and the patient weighed I87 lb. A course of PAS contlnucd for elghty-one days. At the end of this was started on t4.11.49 and discontinued time there was no change i n the radiologlcal eighteen days later on account of intolerance. picture on the left side but the disease in the T o m o g r a p h y at this stage showed multiple right tipper zone had resolved considerably, the cavities in the left lung and postural retention 9 E.S.R., which had been 22/200, fell within a w a s commenced on -o9.II,49 followed by left fortnight to m/o_oo and later to 7/2oo (Westerphrenic crush on ',4.i.5o and the induction of a gren). The sputum became negative for the first pneumoperitoneum on I5.2.5o. A fortnight time for over twelve months and had diminished later there was atelectasis of the whole of the in amount from one ounce to half an ounce left hmg and bronchoscopy showed tuberculous daily. "/'he patient had gained 6 lb. in weight ulceration on the posterior wall of the traclaea and his general condition was so much improved above the bifiircation. The carina was thickened that he was submitted to a left-sided thoracoand there appeared to be complete occlusion plasty with satisfactory results. of the left main-stem bronchus. Streptomycin Case 5- - M r R. J. L., aged 42. Admitted on I g r a m m e daily was given for thirty-eight days. -o8.m.49 with a nine months' history of pulTBI was commenced on-29.4.5o by which time monary tuberculosis; the sputum was "/"/]-+- and the patient weighed i4o lb., the sputum was the E.S.R. 8-I4/2oo (Westergren). X - r a y "l'Bq-, E.S.R. 58/200 (Westergren), a n d x - r a y examination showed infiltration and cavitation examination showed atelectasis of the whole of throughout the whole of the right tipper zone the left lung with multiple underlying cavities; and an early infiltrative lesion in the first the limited lesion on t h e right side was un- intercostal space on the left side. A right-sided
January 1951
TUBERCLE
artificial lmeumothorax was induced on i._,2.5o lint as thoracoscopy showed the apex of the hmg to bc denscly adhercnt the A.P. was abandoned and a phrcnic crush substituted on i8.5.5 o. On ~o.4.5 o the hmg was completely reexpanded and although there had iJeen some radiological clearing there was still a consider-. able amount of exudative disease present in the right upper zone and the limitcd lesion at the left apex persisted. The sputum was T B + and the E.S.R. I4/2oo (Westergren). The patient weighed I5I lb. A course of TBI was commenced on ~9.4.5 o a n d continued for ninety-eight days. At the end of that time the sputum was T B - - and had diminished in amount from half an ounce to a trace daily. The E~S.R. was 6/2oo (Westergren), the weight 143 lb., and the x-ray pictur e showed considerable clearing. Case 6 . - M r D. F., aged 16. Admitted on 17.tl.49 with a history of haemoptysis six months previously following which an x-ray examination showed soft confluent disease throughout the whole of the right hmg. He had been kept in bed Continuously and a course of PAS i8 grammes daily was commenced three weeks before admission. On admission tile sputum was T B + , the E.S.R. 54/2oo (~Vestergren) and an x-ray film showed exudative disease of the right upper zone with probable cavitation. Widespread disease of miliary distribution was present throughout the remainder of the right lung and the left mid and lower zones. PAS 2o grammes daily was given together with streptomycin I gramme daily and on 8.3.50 a pneumoperitoneum was induced. On _07.4.50 there was considerable radiological clearing of the lesion in the left side of tile chest and to a less extent on the right. The sputum was still T B + and the E.S.R. 37/_0oo. The temperature, which had varied from 97 ~ F . - m o ~ F. on admission, was n o w normal and tile patient had gained _0 lb. in weight. There was a trace of sputum daily. A course of TBI was commenced on _09.4.5~ followed by a right phr6nic crush on 4.5.5 o. "/'he TBI was continued for I68 days by which time the sputum was T B - - , the E.S.R. 5/_000 and the x-ray film showed very considerable 9clearing of the lesion in the right upper zone with some appearance of fibrosis; the left hmg was within normal limits. There was now no sputum and the patient lind gained a filrtller I lb. in weight. Case 7 . - Air R. W., aged 32~ Admitted on _0o.x.5o with a history of pulmonary tuberculosis which had been diagnosed six .months previously while undergoing treatment for syphilis. A right-sided artificial pneumothorax had been
II
induced in October 19.t9 and I'AS had been given since tile disease was first diagnosed. The sputtnn was "I'B+ up to October 1949 since when it has been T B - - . On admission the sputum was T B - - , tile E.S.R. 20/2oo (Westergren) a n d an x - r a y of the chest showed a right-slded artificial pneumothorax with complete atelectasis of the right upper lobe. A course of streptomycin I gramme daily was given for fifty days. Bronchoscopy Oil 27.3.5 ~ showed some narrowing of the'i-ight tippet" lobe bronchus. No ulceration was visible and following the emlrse ofstreptomycln fitrther bronchoscopy showed no abnormality in the bronchial tree. On .08.4.50 the sputum was "I'B--, the E.S.R. 22/ooo, and there was no obvious change in the radiological picture, the right upper lobe being still completely 'blackedout'. The patient weighed x6I lb. and produced half an Ounce of sputum daily. A course of TBI was colnmenced on 29.4.5o and was continued for x68 days 1)y wlfich time the E.S.R. was 1I/2OO. (Westergren), tlle sputum was still T B - - and had been reduced to a trace, the patient had lost 4'1, lb. in weight and the radiological picture was unchanged. Case 8 . - M r J . C. W., aged 19. Admitted on 2.9.48 with a history of pulmonary tuberculosis of six months' duration. A right-sided artificial pneumothorax had been induced two months before admission. On admission a shallow right A.P. was present, the sputum was T B + , and the E.S,R. 7/2oo (Westergren). Tomography showed cavitation in the collapsed right upper lobe. Two months later an effusion developed with atelectasis of the right lung. Bronchgscopy showed no obvious abnormality. The efft:sion resolved and the lung re-expanded t o be followed by the appearance of a fresh lesibn in the left apex, for which a left artificial pne~amothorax was induced six months after admission. Th0racoscopy was followed by a left-sided spontaneous pneumothorax and an effusion which caused gradual obliteration of the left A.P. A course of streptomycin i gramme daily for fifty days was given together with PAS oo grammes daily. By December i949 the right lung was completely re-expanded and a loculated pyothorax was present on the left side which was treated with intrapleural PAS and streptomycin without conspicuous success. The sputum was still T B + . In April x95o the fluid on tim left side remained unchanged while the original cavity in the upper zone of the right lung had reappear.ed. The sputum, of which there was half an ounce daily, was T B + a n d t h e organism was resistant to a concentration of 0"025 rag. PAS per ioo mi. medium. The E.S.R. was 17/2oo (Westergren) and the patient ~veighed
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TUBERCLE
r4o lb. Streptomycin resistance had not deVeloped. PAS was discontinued on 22.5.5o and a course o f T B t was commenced on 23.5.5o concurrently with streptomycin I g r a m m e daily, the latter being continued for a further 9 days; TBI was given for 143 day's. By then the sputum was intermittently, T B + and had been reduced to a trace. T h e E.S.R. was 3o]20o (Westergien) and the patient had lost 6 lb. in weight. X - r a y examination showed that there was now no obvious cavitation in the right upper zone but the effusion on the left side persisted. Case 9- - M r H. H. S., aged 49. Admitted on 2.1.5o with a history of pleurisy in 1942 and a haemoptysis in 9 1949. O n admission the sputum was T B + , the E.S.R. 27/2oo (Westergren), and an x-ray film showed bilateral upper zone infiltration with probable cavitation in both apices. A course of PAS 2o grammes daily was begun on 13.2~5o and discontinued after fifteen days on account of sickness and diarrhoea. PAS was started again after a lapse of one month but was discontinued after five" days, and a third attempt one month later had to be abandoned after nineteen days because of intolerance. A course of "I'B~ was commenced on 1.5.5o at which time t h e sputum was T B + , the E.S.R. .o5/2o6 (Westergren), and the x-ray film still showed bilateral upper zone infiltration and probable cavitation. T h e weight was 136 lb., an increase of 8 lb. since admission, and there was one ounce ofsputum daily. 'FBI was continued for 165 days at the end of which time the sputum became T B - - for the first time for nearly a year, the E.S.R. was 16/2oo (Westergren), and the patient had lost 9 xo lb. in weight. T h e amount of sputum was reduced to half an ounce daily but there was no remarkable change in the radiological picture. Case I o . - M r R. V., aged 25. Admitted on 2o.4.5o with a history of pulmonary tuberculofts extending over four )'ears. On admission the sputum was T B + , the E.S.R. 34/2oo (Westergren) and an x-ray film showed fibrocaseous disease in the right uppei" and left mid-zones. T h e weight.on admission was z29 lb. and there was approximately half an ounce of sputum daily. T h e pati.ent had beefi taking PAS 18 grammes daily before admission with no improvement, and this drug was continued, the amount being increased to 2o gi'ammes daily. A course of TBI was begun on z4.7.5o and this was continued together with PAS for ninety-one days. At the end of that time the sputum was still T B + , the E.S.R. 27/2oo (Westergren), and although the patient had gained 4 lb. in weight, and the amount of
January 1951
sputum was reduced to a trace daily, there was no radiological improvement. Case I t . - Air E. F. B., aged 3 L A d m i t t e d on 8.5.5o with a history of pulmonar.y tuberculosis which had been diagnosed nine months previously. T h e patient had been treated at home by rest and a course of PAS lasting for four months. O.n admission the sputum was T B + , the E.S.R. 25/2oo (Westergren), and an x-ray film showed infiltration and cavitation 9 in the right upper zone. The temperature and pulse were normal, the weight I54 lb. and there was half an ounce of sputum daily. A course of TBI and PAS 2o grammes daily was started on 9.6.5 ~ and continued for 126 days. On 26.7.5o a right-sided artificial pneumothorax was induced and a satisfactory collapse obtgined. At the end of the course of TBx and PAS the sputum was T B - - , the E.S.R. 5/2oo (Westergren), and the x-ray showed a satisfactory artificial pneumothorax; the patient had lost nearly, 1 x lb. in weight and was still p r o dueing half an ounce of sputum daily.. 9 Case 1 2 . - Miss M . E. R.; aged 27. Admitted on 13.8.48 with a history of pulmonary tuberculosis extending over twelve months. On admission the s p u t u m - w a s T B + , the E.S.R. 27/200 (Westergren),. and an x-ray showed infiltration and probable cavitation in the left mid-zone with more recent infiltration at the periphery of the right upper zone. O n 6.9.48 a pneumoperitoneum Was induced and is still being maintained. O n 4.x 1.48 a course of PAS was begun and continued for four months. In March x949 a bilateral artificial pneumothorax was induced but abandoned on account of widespread adhesions. On 5.7-49 right phrenic crush was performed. A second course of PAS was begun on 4.zI.49 and continued for six months. A course of streptomycin, i g r a m m e daily, was commenced on 12. 1.5 ~ and continued for fifty-eight days. On 26.4.50 the sputum was T B - - , the E.S.R. 7/2oo (Westergren), there was a trace of sputum daily, and the weight was m 9 lb. An x-ray film then showed very little change from the original film although there was now no obvious cavitation in the left midzone. A course of T B I was started on 28.4.5o and continued for 168 days at the end of which time the sputum was T B - - , the E.S.R. 7/2oo (~,Vestergren), there was still a trace of sputum, and the patient had gained 3 lb. in weight. X - r a y showed slight clearing of the lesions in both hmgs. Toxic Effects T w o patients c o m p l a i n e d o f nausea w i t h o u t a c t u a l vomiting. I n one case this was d u e to
January 1951
T U BERC L E
13
No evidence of peripheral neuritis or any PAS being taken concurrently and ceased when that drug was stopped. Two patients toxic effect on the central nervous system complaincd of loss of appetite and in both was observed, nor was there any instance of cases tile information was volunteered that dermatitis. the loss of appetite concerned fats particuResults larly. The drug was continued and in all cases thcse symptoms cleared up. Gastro- .Apart from tile 4 patients who complainecl intestinal symptoms were extremely mild of listlessness, nausea or loss of appetite in the and in 9 cases did not occur at all. early stages of treatment, no ill-effects were Thr6e female patients complained of felt by any of the patients, who all eventually listlessness and depression, the latter be- experienced tile feeling of well-being usual coming quite marked in 2 cases, but cleared on being given a new form of treatment for up after a few doses of methedrine and did their disease. In 6 cases the cough and not recur. amount of sputum was measurably reduced. Two female patients complained of a Weight. - O u t of the IS patients, 7 lost burning and pricking sensation in the eye- weight, 4 gained, and I remained stationary. balls shortly after treatment had started, The loss in 6 patients varied from 2 to Io but no definite evidence of conjunctivitis lb. In one patient whose condition was was noted and the condition resolved in a rapidly deteriorating, the loss was almost few days. 2 stones. The loss in weigh t appeared to be In 3 cases a mild hypochromic anaemia definitely related to taking the drug as it occurred. There was no remarkable change occurred in patients whose w e i g h t had in the red or white cell counts, ahhough in previously been constant for many months. 6 cases there was a slight fall in the red cell Sputum.- Out of Io patients with a T B + count. No evidence of agranulocytosis was sputum conversion was obtained in 7 cases. seen. The results of sputum cultures, etc., in these In 4 cases a strongly positive colloidal cases are not yet available and it is probable gold reaction was obtained, in one case six that when they are this' "number will be weeks after commencing treatment and in reduced. In 5 of these cases, however, the two others twenty-two days after treatment sputum had been persistently T B + for at had begun. In the fourth case a strongly least six months before commencing treatpositive colloidal gold reaction was obtained ment. before treatment was started and was Erythrocyte Sedimentation Rate. - In IO of tile associated with a positive Kahn test. This I2 patients the E.S.R. fell, in one case it patient had been treated with penicillin for rose and in tim other it remained stationary. syphilis immediately prior to admission. In In most cases the fall took place within the all 4 cases the positive colloidal gold reaction first month and in one patient whose E.S.R. was obtained throughout the course of had ranged from 9o-io5/2oo (Westergren) treatment, although in ~ cases it became for six months the fall was dramatic, weaker after eight and twelve weeks res- reaching 5o/~oo within the first month and pectively. In 4 cascs there was a suggestion of IO[2OO within two months. It is noticeable sallow pigmentation of the skin and in these in this case, how.ever, that on one occasion cases the blood serum was more yellow than when the drug was withdrawn for three usual. There was no definite jaundice, days, the E.S.R. rose to 65/200. however, and the vail den Bergh reaction. Radiological Findings.- In 3 cases there was negative. was considerable radiological clearing 9A cloud of albumen appeared in tim urine (Cases ~, 5 and 6), and in a fourth (Case 8) in ~ cases although there was no filrther a cavity, which had recently appeared and evidence to suggest renal damage. had been unaffected by PAS or streptomycin,
14
January 19SI
T U B E RC L E
rapidly cleared. In the first 3 cases the radio- becomes adapted to the drug. Only if s~,~ logical clearing was accompanied by sputum symptoms perslst should a reductmn ih conversion, while in the fourth case wherein dosage be considered. the sputum had been persistently TB-k- for The optimmn dosage for TBI has yet to eighteen months it was now only inter- be determined, but i5o-.ooo rag. per diet~ mittently T B + . In all these cases the disease seems to be an effective adult dose, and tl~e was of comparatively recent onset, and drug may prove relatively non-toxic in thes apart from the cavitatory case, all were of a anmuuts. Most of the serious toxin effects predominantly exudative nature. reported from German), were associated In 3 cases of a more chronic nature where, with a very much higher dosage. however, the disease was mainly infiltrative A not unimportant advantage of this druin character, there was slight radiological over other anti-tub.erculous agents at preset{g clearing. In the remaining 5 cases, all mainly .m common use ~s xts case of administrati~ n chronic, there was no change in 4, and in and the fhct that there appears to be q~ the fifth an .artificial pneumothorax made comparison with the original film impossible. reason why the drug may not be administere d ovcr prolonged periods. 9
Discussion Although no dramatic claims can be made for TBI the evidence that it is of some value i n the treatment of pulmonary tuberculosis is fairly clear. As with other chemotherapeutic substances its effects appear to be most satisfactory in exudative lesions, and little benefit, if any, was observed in the more chronic type of lesion9 In comparison with other therapeutic agents, TBI appears to have an anti-tuberculous activity somewhat similar to PAS and probably less than streptomycin. In this case there may possibly be a place for its use as a substitute in cases of intolerance or idiosyncrasy to PAS. In 2 cases in which TBI and PAS were given together it could not be said that there was any additive effect, and in the case whe/e TBI and streptomycin were given concurrently streptomycin resistance developed, unaffected apparently by the use o f TBI. In this short series none o[" the serious toxic effects reported by the German workers were encountered, but it is felt ttiat at present the drug should only be administered under strict laboratory control. T h e mild gastro-intestinal upsets, depression and subjective ocular symptoms all seem to be transitory phenomena, not due to overdosage but disappearing in the course of the first few weeks of treatment as the body
9
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References [I] Domagh, G., Behni_sch, R., Mictz_~che, F., a~, Schmklt, II. (i946) .A'aturwt~sensehaften, xxxm, .,~u 9
O
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[2] Dram, D.J., Goodacre, C. L., and Seymour, I)..i.. 0949) .yourn. Pharm., t, 784 . " "" [3] Domagh, G. 095o) Amer. Rev. Tubeic., Lxh 8. [4] Dornagh, G. (195o) Amer. Rev. Tubere., LXl, 8. [5] Levadlti, C. (t919) Press9 ,lied., I.vH, 519. [61 Illnshaw, 11. C., and McDermott, W9 (t95o) Amer Rev. 7-uberc., i_xt, 145.
Correspondence "l'he Editor - 'Tubercle'. S I R , - On November 24 melnbers of tl~ British Tuberculosis Assoelatton assembled at Manson House anticipating a discussion ovL the use of Mass Radiography. Dr Peter Kerley speaking first, reviewed the history of civiliaq Mass Miniature Radiography, discussed teetl. nique, gave us a timely warning to eschew badl). taken films and told us that if we had a clear chest x-ray at the age of 4 ~ we had no further need to worry. Dr Norman Smith clothed so~/e dry bones but no one responded to his invitation to breathe life into them. After tea Dr Owen Clarke in a witty paper skilfully avoided committing himself on the subject at all by speaking on an entirely different one. Dr Hoffstaedt then occupied much time discussing the cost of Mass Miniatm9 Radio. graphy based on the work of Units making O~ly 25,000 examinations per )'cat'. l'\[~lIly Units in this country double this figure in a )'ear. It Was then left to Dr Trenchard at a late hour to 9
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A compromise scheme might be based on the following points: (I) Future planning should concentrate on areas with a proved high incidence of tuberculosis. (2) In these areas, surveys of organized groups should be annual, or bi-annual, and be followed by extensive open sessions for the public. (3) In areas of a lesser incidence of tuberculosis and where mass surveys of
January 1951
organized groups have already taken place in the past, follow-up examinations should be considerably curtailed and replaced by open public sessions at intervals determined by the number of tuberculous found. (4) Priority for the under 35 s should be asked for in all follow-up surveys, although it is realized that arrangements to this effect are not always easy to make.
Thiosemicarbazones in the Treatment of Pulmonary Tuberculosis By ROBERT LIVINGSTONE
Physician Superintendent and EDMUND W . STREET
Senior Assistant Medical Officer, Lenham Sanatorium Of recent years considerable interest has been aroused, particularly in Germany, by theuseofthiosemicarbazones in the treatment of pulmonary and other forms of tuberculosis. Of the series of thiosemicarbazones investigated by Domagh and his colleagues [I], para-acetylamino benzaldehyde thiosemicarbazone (TBI) has given the most encouraging results, hz vitro experiments by Drain and others [2] using a modified Dubos' medium showed that the drug possessed an inhibitory effect on M. tubemtlosis, strain H37RV , in a concelatration of the order of o.o5-o.i mg. per I OO rot. medium. This activity appears to be unaffected by the presence of para-aminobenzoic acid [3]. Experiments by Domagh [4] and Levaditi [5] on animals with induced tuberculosis have shown TBI to have a definite suppressive action. At present extensive use of the drug has been confined almost exclusively to Germany and the results have been considered in detail by Hinshaw and McDermott [6] who consider that the results justify controlled trials. In an evaluation of the results in 64 patients suffering from acute forms of pulmonary tuberculosis these writers found
decided improvement in 59 per cent of cases and partial improvement in x9 per cent, while in 2 2 p e r cent of cases there was no change. In chronic forms of the disease they report that of 57 patients marked improvement was observed in 5 per cent, partial improvement in 28 per cent, while in 67 per cent of cases there was no change. In another i36 patients there was improvement in recent or progressive lesions in 19 cases (I 4 per cent), shrinkage of cavities in 7 (5 per cent), sputum conversion in I2 (8. 9 per cent), reduction in temperature in 28 (2o. 5 per cent), iinprovement in the sedimentation rate in 27 (I9.8 per cent), and collapse therapy made possible in 7 cases (5 per cent). In a further 94 cases evaluated they report striking convincing improvement in 29 cases (3o.8 per cent), and probable evidence of good result in I8 cases (I9 per cent). Wifll regard to toxic effects Hinshaw and McDermott report that anorexia, malaise, and occasional vomiting were fairly common; these symptoms appeared to be related to the amount of drug given and subsided when the dose was reduced. An unknown percentage of patients developed mild anaemia
January 1951
TUBERCLE
Dosage and mention is made of a few cases with haemolytic reactioris due presumably to All patients, commenced with one 5 ~ ing. excessive dosage. Agranulocytosis was re- tablet daily for three days, two 5 ~ mg. ported in 8 cases among 2,ooo patients but tablets daily for the next three days, and several of these were receiving aminopyrine fQur 5 ~ nag. tablets daily thereafter. In Case at the time agranulocytosis developed. 6 nausea permitted only three tablets (i5o Several cases of mild albuminuria were mg.) to be taken daily, while in Cases 7, 8, 9, reported but in no case was definite renal IO and I I the daily dose was raised to six damage apparent, Skin rashes appeared to tablets (300 mg.) after three months without be fairly common but rarely severe. In a ill-effect. The tablets were given either one considerable number of cases jaundice "or two at a time after meals, and treatment occurred and although there was consider- was in most cases continuous for up to five able confusion as to its origin, in many months. instances it could be attributed to the use of During t h e investigation sputum and TBI. The jaundice appeared to be d u e to x:ray examinations were done at monthly fatty infiltration and in the opinion of most intervals. A complete blood count was done observers the change was reversible. .monthly and a differential white count at ~;eekly intervals. Also at weekly intervals an estimation was made of the serum proteins, Material In view of these encouraging results T B I serum alkaline phosphatase and blood urea. was tried out on I2 patients. The actual The colloidal gold reaction was also done drug used is marketed under the name weekly. The blood chemistry will be the 'Thioparamizone' and is available in tablets subject of a future communication. of 5 ~ mg. O f the z2 patients, 7 were male Case Reports and 5 female. 3 patients suffered from relaCase I . M r s F. C., aged 33. Admitted on tively recent disease (Cases 2, 5 and 6), 7 12.ix.49 With a h!story pulmonary tubercufrom more chronic disease (Cases I, 4, 8, 9, losis extending over twoofyears. X-ray showed xo, z z and z2), and 2 were suffering.from widespread fibrocaseous disease throughout the endobronchial tuberculosis (Cases 3 and 7). whole of the left lung, with infiltration and Apart from Case z where treatment was cavitation in the upper zone of the right lung. started one month after admission, all cases There was also present 'a pneumopentor~eum which had been induced thi'ee months previously. had previously been under observation for Sputum T B + , E.S.K. 92[2oo (Westergren), at least three months, and had had various evening temperature IOO~ F., pulse I t2, x~'eight other forms of active and chemotherapeutic 96 lb. The patient was very thin and pale and a measures t r i e d wittkout any remarkable moderate degree of toxaemia was presen t. A success. All cases apart from Case 5 had had course of PAS 2o grammes daily was commenced three days after admission and continued for a course of PAS previously, Cases 3, 6 and 7 five and a half months. By this time the patient's had had streptomycin, Cases 7 and 8, temperature was normal, pulse 92 , sputum artificial pncumothorax, Cases I, 3, 6 and z2, T B + , E.S.R. 95/2oo (Westergren), weight pneumoperitoneum, and Case 3, postural Io9 lb. There was no appreciable radio log'ical retention. In Cases IO and I I, PAS was also change. The organism was now resistant to a given concurrently with TBI, and in Case 8 concentration of 6"4 rag. PAS per Too ml. medium.' PAS was stopped and TBx was comstreptomycin z gramme daily was given menced on ~9.4.5 o and continued for I5I days. concurrently. Case I I had a right artificial The most noticeable effect was the rapid fall in the E.S.R. which dropped from 95/200 to pneumothorax induced and maintained during the course of treatment. The pro- 52/2oo in fourteen days, having previously longed observation p e r i o d prior to com- remained at an average level of 97[2oo for six months. Thereafter the E.S.R. progressively fell mencing treatment no doubt accounts for and two months later was zo/2oo and remained the fact that none of the patients was febrile, at that level throughout the course of treatment.
I0
TUBERCLE
January 1951
At the end of five antl a half months' treatment changed. On ~3.6.5o, forty-threc days aficr tile the Sl)Utum rcmaincd "I'B-~- and there was very course of streptomycin had bccn c()mplcted and little change in the radiological picture ,,f the tbrty-t})ur days after commencing '/'Ill l)ronchohmgs. The weight had drol?pcd to m I lb., and scopy showed the tracheal ulceration to have the daily amount of sputum was unchanged. healed completely and the left main-stem bronCase 2 . - Mrs L. H., aged 23. Admitted on elms was now patent. After five and a half 5.,t.5 ~ following a small haemoptysis three months' treatment with TBI t h e sputum was months previously. The patient had been still T B + , tile E.S.R. had fallen to i3/2oo , and continuously in bed for three months before tile x-ray fihn showed re-aeration of tile left admission. X-ray showed scattered infiltration h m g which, however, contained m a n y large throughout the upper zone of the left lung; cavities; the lesion on the right side was sputum TBq-, E.S.R. 3/2oo (Westergren). The practically unchanged. During the course of general condition was fair, pulse and tempera, treatment the patient continued progressively ture were within normal limits, and there were to lose weight and at the end of the course no signs of toxicity. PAS 20 grammes daily was weighed I 15 lb., a loss of_o5 lb. given from 20.4.50 and TBI from 29.,1.5o. Case 4- - Mr S. K. L., aged 33. Admitted on PAS was discontinued after twenty-six days 27.x.5 o with a history of pulmonary tubercubecause of nausea which ceased when PAS was losis extending over six years. Before admission stopped. '/'he sputum became T B - - seventy he had been on bed rest and PAS i8-grammes days after treatment had commenced and has daily for six months and a left phrenic crusl~ remained so. After five and a half months' had been performed three months prior to treatment the x-ray picture shows very con- admission. It was considered that in view of the siderable clearing although some infiltration chronic nature of the disease further treatment persists in the left upper zone. The amount o was unlikely to be of benefit. On admission the sputum has been reduced from half an ounce sputum was T B + , E.S.R. 24/2oo (Westergren), daily to a trace and the patient has gained 3 lb. and the x-ray picture showed widespread fibroin weight. caseous disease throughout the whole of the left C a s e " 3 . - Mrs J. E,., aged 24. Admitted on hmg w i t h more recent progressive exudative i I.Io.49 with a history of pulmonary tubercu- disease of the right upper zone. "/'he temperature losis extending over twelve months. Serial and pulse were normal and t h e weight was x-rays showed progressive parenchymal disease 154 lb. During the next three months the on the left side d u r i n g this time in spite of condition of the disease in the left lung remained continued bed rest. On admission an x-ray unchanged but the right side of the chest showed scattered exudative lesions throughout showed a progressive if slow increase in the the whole of t h e left lung and an area of fine infiltrative lesion. On sputum culture the mottling at the periphery of the .right mid-zone. organism was found to be resistant to a conThe sputum was T B + , E.S.R. 46/2oo (Wester- centration of 3.2 rag. PAS per IOO ml. medium. gren). The evening temperature was 99 ~ F. and A course of TBI was commenced on 8.5.5o and the patient weighed I87 lb. A course of PAS contlnucd for elghty-one days. At the end of this was started on t4.11.49 and discontinued time there was no change i n the radiologlcal eighteen days later on account of intolerance. picture on the left side but the disease in the T o m o g r a p h y at this stage showed multiple right tipper zone had resolved considerably, the cavities in the left lung and postural retention 9 E.S.R., which had been 22/200, fell within a w a s commenced on -o9.II,49 followed by left fortnight to m/o_oo and later to 7/2oo (Westerphrenic crush on ',4.i.5o and the induction of a gren). The sputum became negative for the first pneumoperitoneum on I5.2.5o. A fortnight time for over twelve months and had diminished later there was atelectasis of the whole of the in amount from one ounce to half an ounce left hmg and bronchoscopy showed tuberculous daily. "/'he patient had gained 6 lb. in weight ulceration on the posterior wall of the traclaea and his general condition was so much improved above the bifiircation. The carina was thickened that he was submitted to a left-sided thoracoand there appeared to be complete occlusion plasty with satisfactory results. of the left main-stem bronchus. Streptomycin Case 5- - M r R. J. L., aged 42. Admitted on I g r a m m e daily was given for thirty-eight days. -o8.m.49 with a nine months' history of pulTBI was commenced on-29.4.5o by which time monary tuberculosis; the sputum was "/"/]-+- and the patient weighed i4o lb., the sputum was the E.S.R. 8-I4/2oo (Westergren). X - r a y "l'Bq-, E.S.R. 58/200 (Westergren), a n d x - r a y examination showed infiltration and cavitation examination showed atelectasis of the whole of throughout the whole of the right tipper zone the left lung with multiple underlying cavities; and an early infiltrative lesion in the first the limited lesion on t h e right side was un- intercostal space on the left side. A right-sided
January 1951
TUBERCLE
artificial lmeumothorax was induced on i._,2.5o lint as thoracoscopy showed the apex of the hmg to bc denscly adhercnt the A.P. was abandoned and a phrcnic crush substituted on i8.5.5 o. On ~o.4.5 o the hmg was completely reexpanded and although there had iJeen some radiological clearing there was still a consider-. able amount of exudative disease present in the right upper zone and the limitcd lesion at the left apex persisted. The sputum was T B + and the E.S.R. I4/2oo (Westergren). The patient weighed I5I lb. A course of TBI was commenced on ~9.4.5 o a n d continued for ninety-eight days. At the end of that time the sputum was T B - - and had diminished in amount from half an ounce to a trace daily. The E~S.R. was 6/2oo (Westergren), the weight 143 lb., and the x-ray pictur e showed considerable clearing. Case 6 . - M r D. F., aged 16. Admitted on 17.tl.49 with a history of haemoptysis six months previously following which an x-ray examination showed soft confluent disease throughout the whole of the right hmg. He had been kept in bed Continuously and a course of PAS i8 grammes daily was commenced three weeks before admission. On admission tile sputum was T B + , the E.S.R. 54/2oo (~Vestergren) and an x-ray film showed exudative disease of the right upper zone with probable cavitation. Widespread disease of miliary distribution was present throughout the remainder of the right lung and the left mid and lower zones. PAS 2o grammes daily was given together with streptomycin I gramme daily and on 8.3.50 a pneumoperitoneum was induced. On _07.4.50 there was considerable radiological clearing of the lesion in the left side of tile chest and to a less extent on the right. The sputum was still T B + and the E.S.R. 37/_0oo. The temperature, which had varied from 97 ~ F . - m o ~ F. on admission, was n o w normal and tile patient had gained _0 lb. in weight. There was a trace of sputum daily. A course of TBI was commenced on _09.4.5~ followed by a right phr6nic crush on 4.5.5 o. "/'he TBI was continued for I68 days by which time the sputum was T B - - , the E.S.R. 5/_000 and the x-ray film showed very considerable 9clearing of the lesion in the right upper zone with some appearance of fibrosis; the left hmg was within normal limits. There was now no sputum and the patient lind gained a filrtller I lb. in weight. Case 7 . - Air R. W., aged 32~ Admitted on _0o.x.5o with a history of pulmonary tuberculosis which had been diagnosed six .months previously while undergoing treatment for syphilis. A right-sided artificial pneumothorax had been
II
induced in October 19.t9 and I'AS had been given since tile disease was first diagnosed. The sputtnn was "I'B+ up to October 1949 since when it has been T B - - . On admission the sputum was T B - - , tile E.S.R. 20/2oo (Westergren) a n d an x - r a y of the chest showed a right-slded artificial pneumothorax with complete atelectasis of the right upper lobe. A course of streptomycin I gramme daily was given for fifty days. Bronchoscopy Oil 27.3.5 ~ showed some narrowing of the'i-ight tippet" lobe bronchus. No ulceration was visible and following the emlrse ofstreptomycln fitrther bronchoscopy showed no abnormality in the bronchial tree. On .08.4.50 the sputum was "I'B--, the E.S.R. 22/ooo, and there was no obvious change in the radiological picture, the right upper lobe being still completely 'blackedout'. The patient weighed x6I lb. and produced half an Ounce of sputum daily. A course of TBI was colnmenced on 29.4.5o and was continued for x68 days 1)y wlfich time the E.S.R. was 1I/2OO. (Westergren), tlle sputum was still T B - - and had been reduced to a trace, the patient had lost 4'1, lb. in weight and the radiological picture was unchanged. Case 8 . - M r J . C. W., aged 19. Admitted on 2.9.48 with a history of pulmonary tuberculosis of six months' duration. A right-sided artificial pneumothorax had been induced two months before admission. On admission a shallow right A.P. was present, the sputum was T B + , and the E.S,R. 7/2oo (Westergren). Tomography showed cavitation in the collapsed right upper lobe. Two months later an effusion developed with atelectasis of the right lung. Bronchgscopy showed no obvious abnormality. The efft:sion resolved and the lung re-expanded t o be followed by the appearance of a fresh lesibn in the left apex, for which a left artificial pne~amothorax was induced six months after admission. Th0racoscopy was followed by a left-sided spontaneous pneumothorax and an effusion which caused gradual obliteration of the left A.P. A course of streptomycin i gramme daily for fifty days was given together with PAS oo grammes daily. By December i949 the right lung was completely re-expanded and a loculated pyothorax was present on the left side which was treated with intrapleural PAS and streptomycin without conspicuous success. The sputum was still T B + . In April x95o the fluid on tim left side remained unchanged while the original cavity in the upper zone of the right lung had reappear.ed. The sputum, of which there was half an ounce daily, was T B + a n d t h e organism was resistant to a concentration of 0"025 rag. PAS per ioo mi. medium. The E.S.R. was 17/2oo (Westergren) and the patient ~veighed
12
TUBERCLE
r4o lb. Streptomycin resistance had not deVeloped. PAS was discontinued on 22.5.5o and a course o f T B t was commenced on 23.5.5o concurrently with streptomycin I g r a m m e daily, the latter being continued for a further 9 days; TBI was given for 143 day's. By then the sputum was intermittently, T B + and had been reduced to a trace. T h e E.S.R. was 3o]20o (Westergien) and the patient had lost 6 lb. in weight. X - r a y examination showed that there was now no obvious cavitation in the right upper zone but the effusion on the left side persisted. Case 9- - M r H. H. S., aged 49. Admitted on 2.1.5o with a history of pleurisy in 1942 and a haemoptysis in 9 1949. O n admission the sputum was T B + , the E.S.R. 27/2oo (Westergren), and an x-ray film showed bilateral upper zone infiltration with probable cavitation in both apices. A course of PAS 2o grammes daily was begun on 13.2~5o and discontinued after fifteen days on account of sickness and diarrhoea. PAS was started again after a lapse of one month but was discontinued after five" days, and a third attempt one month later had to be abandoned after nineteen days because of intolerance. A course of "I'B~ was commenced on 1.5.5o at which time t h e sputum was T B + , the E.S.R. .o5/2o6 (Westergren), and the x-ray film still showed bilateral upper zone infiltration and probable cavitation. T h e weight was 136 lb., an increase of 8 lb. since admission, and there was one ounce ofsputum daily. 'FBI was continued for 165 days at the end of which time the sputum became T B - - for the first time for nearly a year, the E.S.R. was 16/2oo (Westergren), and the patient had lost 9 xo lb. in weight. T h e amount of sputum was reduced to half an ounce daily but there was no remarkable change in the radiological picture. Case I o . - M r R. V., aged 25. Admitted on 2o.4.5o with a history of pulmonary tuberculofts extending over four )'ears. On admission the sputum was T B + , the E.S.R. 34/2oo (Westergren) and an x-ray film showed fibrocaseous disease in the right uppei" and left mid-zones. T h e weight.on admission was z29 lb. and there was approximately half an ounce of sputum daily. T h e pati.ent had beefi taking PAS 18 grammes daily before admission with no improvement, and this drug was continued, the amount being increased to 2o gi'ammes daily. A course of TBI was begun on z4.7.5o and this was continued together with PAS for ninety-one days. At the end of that time the sputum was still T B + , the E.S.R. 27/2oo (Westergren), and although the patient had gained 4 lb. in weight, and the amount of
January 1951
sputum was reduced to a trace daily, there was no radiological improvement. Case I t . - Air E. F. B., aged 3 L A d m i t t e d on 8.5.5o with a history of pulmonar.y tuberculosis which had been diagnosed nine months previously. T h e patient had been treated at home by rest and a course of PAS lasting for four months. O.n admission the sputum was T B + , the E.S.R. 25/2oo (Westergren), and an x-ray film showed infiltration and cavitation 9 in the right upper zone. The temperature and pulse were normal, the weight I54 lb. and there was half an ounce of sputum daily. A course of TBI and PAS 2o grammes daily was started on 9.6.5 ~ and continued for 126 days. On 26.7.5o a right-sided artificial pneumothorax was induced and a satisfactory collapse obtgined. At the end of the course of TBx and PAS the sputum was T B - - , the E.S.R. 5/2oo (Westergren), and the x-ray showed a satisfactory artificial pneumothorax; the patient had lost nearly, 1 x lb. in weight and was still p r o dueing half an ounce of sputum daily.. 9 Case 1 2 . - Miss M . E. R.; aged 27. Admitted on 13.8.48 with a history of pulmonary tuberculosis extending over twelve months. On admission the s p u t u m - w a s T B + , the E.S.R. 27/200 (Westergren),. and an x-ray showed infiltration and probable cavitation in the left mid-zone with more recent infiltration at the periphery of the right upper zone. O n 6.9.48 a pneumoperitoneum Was induced and is still being maintained. O n 4.x 1.48 a course of PAS was begun and continued for four months. In March x949 a bilateral artificial pneumothorax was induced but abandoned on account of widespread adhesions. On 5.7-49 right phrenic crush was performed. A second course of PAS was begun on 4.zI.49 and continued for six months. A course of streptomycin, i g r a m m e daily, was commenced on 12. 1.5 ~ and continued for fifty-eight days. On 26.4.50 the sputum was T B - - , the E.S.R. 7/2oo (Westergren), there was a trace of sputum daily, and the weight was m 9 lb. An x-ray film then showed very little change from the original film although there was now no obvious cavitation in the left midzone. A course of T B I was started on 28.4.5o and continued for 168 days at the end of which time the sputum was T B - - , the E.S.R. 7/2oo (~,Vestergren), there was still a trace of sputum, and the patient had gained 3 lb. in weight. X - r a y showed slight clearing of the lesions in both hmgs. Toxic Effects T w o patients c o m p l a i n e d o f nausea w i t h o u t a c t u a l vomiting. I n one case this was d u e to
January 1951
T U BERC L E
13
No evidence of peripheral neuritis or any PAS being taken concurrently and ceased when that drug was stopped. Two patients toxic effect on the central nervous system complaincd of loss of appetite and in both was observed, nor was there any instance of cases tile information was volunteered that dermatitis. the loss of appetite concerned fats particuResults larly. The drug was continued and in all cases thcse symptoms cleared up. Gastro- .Apart from tile 4 patients who complainecl intestinal symptoms were extremely mild of listlessness, nausea or loss of appetite in the and in 9 cases did not occur at all. early stages of treatment, no ill-effects were Thr6e female patients complained of felt by any of the patients, who all eventually listlessness and depression, the latter be- experienced tile feeling of well-being usual coming quite marked in 2 cases, but cleared on being given a new form of treatment for up after a few doses of methedrine and did their disease. In 6 cases the cough and not recur. amount of sputum was measurably reduced. Two female patients complained of a Weight. - O u t of the IS patients, 7 lost burning and pricking sensation in the eye- weight, 4 gained, and I remained stationary. balls shortly after treatment had started, The loss in 6 patients varied from 2 to Io but no definite evidence of conjunctivitis lb. In one patient whose condition was was noted and the condition resolved in a rapidly deteriorating, the loss was almost few days. 2 stones. The loss in weigh t appeared to be In 3 cases a mild hypochromic anaemia definitely related to taking the drug as it occurred. There was no remarkable change occurred in patients whose w e i g h t had in the red or white cell counts, ahhough in previously been constant for many months. 6 cases there was a slight fall in the red cell Sputum.- Out of Io patients with a T B + count. No evidence of agranulocytosis was sputum conversion was obtained in 7 cases. seen. The results of sputum cultures, etc., in these In 4 cases a strongly positive colloidal cases are not yet available and it is probable gold reaction was obtained, in one case six that when they are this' "number will be weeks after commencing treatment and in reduced. In 5 of these cases, however, the two others twenty-two days after treatment sputum had been persistently T B + for at had begun. In the fourth case a strongly least six months before commencing treatpositive colloidal gold reaction was obtained ment. before treatment was started and was Erythrocyte Sedimentation Rate. - In IO of tile associated with a positive Kahn test. This I2 patients the E.S.R. fell, in one case it patient had been treated with penicillin for rose and in tim other it remained stationary. syphilis immediately prior to admission. In In most cases the fall took place within the all 4 cases the positive colloidal gold reaction first month and in one patient whose E.S.R. was obtained throughout the course of had ranged from 9o-io5/2oo (Westergren) treatment, although in ~ cases it became for six months the fall was dramatic, weaker after eight and twelve weeks res- reaching 5o/~oo within the first month and pectively. In 4 cascs there was a suggestion of IO[2OO within two months. It is noticeable sallow pigmentation of the skin and in these in this case, how.ever, that on one occasion cases the blood serum was more yellow than when the drug was withdrawn for three usual. There was no definite jaundice, days, the E.S.R. rose to 65/200. however, and the vail den Bergh reaction. Radiological Findings.- In 3 cases there was negative. was considerable radiological clearing 9A cloud of albumen appeared in tim urine (Cases ~, 5 and 6), and in a fourth (Case 8) in ~ cases although there was no filrther a cavity, which had recently appeared and evidence to suggest renal damage. had been unaffected by PAS or streptomycin,
14
January 19SI
T U B E RC L E
rapidly cleared. In the first 3 cases the radio- becomes adapted to the drug. Only if s~,~ logical clearing was accompanied by sputum symptoms perslst should a reductmn ih conversion, while in the fourth case wherein dosage be considered. the sputum had been persistently TB-k- for The optimmn dosage for TBI has yet to eighteen months it was now only inter- be determined, but i5o-.ooo rag. per diet~ mittently T B + . In all these cases the disease seems to be an effective adult dose, and tl~e was of comparatively recent onset, and drug may prove relatively non-toxic in thes apart from the cavitatory case, all were of a anmuuts. Most of the serious toxin effects predominantly exudative nature. reported from German), were associated In 3 cases of a more chronic nature where, with a very much higher dosage. however, the disease was mainly infiltrative A not unimportant advantage of this druin character, there was slight radiological over other anti-tub.erculous agents at preset{g clearing. In the remaining 5 cases, all mainly .m common use ~s xts case of administrati~ n chronic, there was no change in 4, and in and the fhct that there appears to be q~ the fifth an .artificial pneumothorax made comparison with the original film impossible. reason why the drug may not be administere d ovcr prolonged periods. 9
Discussion Although no dramatic claims can be made for TBI the evidence that it is of some value i n the treatment of pulmonary tuberculosis is fairly clear. As with other chemotherapeutic substances its effects appear to be most satisfactory in exudative lesions, and little benefit, if any, was observed in the more chronic type of lesion9 In comparison with other therapeutic agents, TBI appears to have an anti-tuberculous activity somewhat similar to PAS and probably less than streptomycin. In this case there may possibly be a place for its use as a substitute in cases of intolerance or idiosyncrasy to PAS. In 2 cases in which TBI and PAS were given together it could not be said that there was any additive effect, and in the case whe/e TBI and streptomycin were given concurrently streptomycin resistance developed, unaffected apparently by the use o f TBI. In this short series none o[" the serious toxic effects reported by the German workers were encountered, but it is felt ttiat at present the drug should only be administered under strict laboratory control. T h e mild gastro-intestinal upsets, depression and subjective ocular symptoms all seem to be transitory phenomena, not due to overdosage but disappearing in the course of the first few weeks of treatment as the body
9
'e
References [I] Domagh, G., Behni_sch, R., Mictz_~che, F., a~, Schmklt, II. (i946) .A'aturwt~sensehaften, xxxm, .,~u 9
O
,~.
[2] Dram, D.J., Goodacre, C. L., and Seymour, I)..i.. 0949) .yourn. Pharm., t, 784 . " "" [3] Domagh, G. 095o) Amer. Rev. Tubeic., Lxh 8. [4] Dornagh, G. (195o) Amer. Rev. Tubere., LXl, 8. [5] Levadlti, C. (t919) Press9 ,lied., I.vH, 519. [61 Illnshaw, 11. C., and McDermott, W9 (t95o) Amer Rev. 7-uberc., i_xt, 145.
Correspondence "l'he Editor - 'Tubercle'. S I R , - On November 24 melnbers of tl~ British Tuberculosis Assoelatton assembled at Manson House anticipating a discussion ovL the use of Mass Radiography. Dr Peter Kerley speaking first, reviewed the history of civiliaq Mass Miniature Radiography, discussed teetl. nique, gave us a timely warning to eschew badl). taken films and told us that if we had a clear chest x-ray at the age of 4 ~ we had no further need to worry. Dr Norman Smith clothed so~/e dry bones but no one responded to his invitation to breathe life into them. After tea Dr Owen Clarke in a witty paper skilfully avoided committing himself on the subject at all by speaking on an entirely different one. Dr Hoffstaedt then occupied much time discussing the cost of Mass Miniatm9 Radio. graphy based on the work of Units making O~ly 25,000 examinations per )'cat'. l'\[~lIly Units in this country double this figure in a )'ear. It Was then left to Dr Trenchard at a late hour to 9
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(~