78

TEBAFEN IN PULMONARY TUBERCULOSIS

By C. S. BREATHNACH, M.B., B.Ch.

(Dub l in Regional Chest Hospi ta l , Blanahardstow~.)

S INCE the beginning of this century synergic action has been sought falter by pharmacologists with a tenacity equal to that of the alchemists who searched in bygone days for the philosopher's stone.

Practical proof of its feasability was given by the fruitful combination of such simple drugs as acetyl salicylic acid, phenacetin and codein, and very recently a similar triad has been found in chlorpromazine, pro- methazine and pethidine. In antimicrobial warfare synergistic effects xvere also demonstrated, but group antagonism was also discovered shortly after the arrival of the first cluster of broad-spectrum antibiotics. Therapeutic trial of all proposed combinations is therefore essential.

The need for protection of isonicotinyl hydrazide (I.N.H.) was soon apparent after its introduction and both streptomycin and para-amino- salicylic acid (P.A.S.) were shown to be very successful in this r e g a r d - (Joiner et al., ~ Medical Research Council~). Thiosemicarbazone and its derivatives were known to have undoubted antituberculous propertie~-- 1)omagk et al., :~ and had in fact been shown to synergise with P.A.S.-- Heilmeyer ~ and Ptaszynski and Salvi. ~ Domagk ~ was aware of Heilmeyer's results and proposed the use of streptomycin with Conteben

T A B L E IA/ Clinical Progre.~s.

Pa t i en t

No. ] B.R.

No. ? W . K .

:No. 3 P.B.

No. 4 W.O.D.

No. 5 E.S.

No. 6 A.C.

(3bange in General

Condition

good

good

very good

no cnange

fair

very good

Weight (lb.)

I, mon ths 6 mon ths

137 15]

120 134

109 ]09

126 134

98

84 120

E.S.I~, (ram. in 1 hr.) (Westergren)

0 mon ths 6 months

20 6

78 58

55 3

16 38

15 4

50 18

T A B L E IB. Haematological Control.

Pat ien t

No, 1 B,R.

Red Blood Cells White Blood Cells

0 mon ths 3 mon ths

5,140,000 5,420,000

4,050,000

4,670,000 5,180,000

4,380,000 4,500,0(;0

4,130,000 4,680,00,.

3 months 0 mon t hs 1 month

9,000 8,400

7,650 8,650

9,000 7,100

11,300 6,500

21,0C0 23,350

7,400

:No, 2 W.K . 10,250

No, 3 P.B. 7,850

:No, 5 E.S. 7,400

No. 6 A.C. 8,900

'" T E B A F E N " I N P U L M O N A R Y T U B E R C U L O S I S

TABLE IC. Radiological Progress.

79

r a t l e n t

o . 1 B . R .

No. 2 W.K.

No. 3 P.B.

~ o . 4

W.O.D.

No. 5 E.S.

No. 6 A.C.

Radiological Condition

R.U.L. atelectasis wi th recent spread to L. midzone.

R.U.L. large tension cavity with sur- rounding infiltra - t ion ; slight mot- t l ing L.U.L,

R.U.L. large tension cavity wi th some mott l ing scat tered through bo th U.L.

R.U.L. cavi ta t ion with intense sur- rounding fibrosis.

Destroyed L.U.L. wi th acute eavi- t a red spread to R.U.L.

R.U.L. excava ted wi th sp read to base. two smallcavi t ies at L. apex.

TABLES I, I I . l~acteriological Progress.

I .N-H. Sensitivity

Radiological Change I.

.Patient

No, 1 B.R.

No. 2 W.K.

No. 3 P.B.

No. 4 W.O.D.

No. 5 E.S.

No. 6 A.C.

Sputum

0 months

+1)

--1)

+1)

+ D

3 months

--1)

:h i )

Culture negative

Sensitive

Sensitive

Culture negat ive

Resis tant

Sensitive

1I No. Sput ,nn

mon!hs 17i)2 +1) 2G .

;3-----5:

~Posi t ive . _4= = I n t e r - mi t te~t positive.

-- ---- negative. D =1)i rect examination. C = Culture. G.L. =Gas t r i c Lavage.

- - t i l e m o s t p o t e n t of t h e t h i o s e m i c a r b a z o n e s . N o t s u r p r i s i n g l y , t h e n , t h e s i m u l t a n e o u s u s e of b o t h I . N . H . a n d a t h i o s e m i c a r b a z o n c s h o u l d come to m i n d a n d be c o n s i d e r e d w o r t h y of t r i a l . I n p h y s i c a l c o m b i n a t i o n v e r y s a t i s f a c t o r y r e s u l t s h a v e b e e n r e p o r t e d b y L a n g e r 7 a n d b y R u z i c z k a ~ in c l i n i c a l t r i a l s a n d i n l a b o r a t o r y e x p e r i m e n t s b y H i r s c h . 9 R e p o r t s too, h a v e b e e n f u r n i s h e d b y C o n a l t y a n d O ' B r i e n 1~ f o l l o w i n g t h e use of a

80 I R I S H JOURNAL OF MEDICAL S CIEN CE

synthetic polymer of the two substances and starch, and from the survey " it was claimed only that the new drug was worthy of t r ia l ."

In Rialto Hospital and, since its closure, in the Regional Chest Hospital, Blanchardstown, a limited trial, which was divided into two sections, of "Tebafen " (or G.T.3) was carr ied out. Tebafen is a physical mixture of 10 mgm. nicotinaldehyde thiosemicarbazone and 40 mgm. I.N.H. presented in a single tablet.* At the outset this preparat ion was administered to 6 patients for three months af ter which they were t reated by rest ahme for another three months. Careful haematological watch was maintained while chemotherapy was in progress, and bacteriological sensit ivity tests were conducted on specimens of sputum collected towards the end of the 6-month period when reversion might be expected to have begun to take place.

The satisfactory results prompted the second division of the trial which was under taken in view of the inadequate synergy and mutual protection when daily I.N.H. was combined with twice weekly streptomycin. Reiteration of the Medical Research Council 's (1955) results 1~ in this regard may not be out of place.

I. N. t t . Resistance : At 2 m o n t h s no res is tant s t ra in was found in 43 posit ive cul- tu res f rom pat ients on cont inuous s t rep tomycin and I . N . H . , whereas 6 of 59 posit ive cultures were res is tant among the in te rmi t t en t s t r ep tomyc in group. At 3 m o n t h s 2 of 22 posit ives f rom the cont inuous group and 12 of 30 cultures positive f rom the in- t e rmi t t en t group were res is tant . Expres sed as percentage of the tota l n u m b e r of pa t ien ts for w h o m culture was under taken , res is tant s t rahls were isolated f rom 2 per cent. of the cont inuous group and 9 per cent. of the in te rmi t ten t . At 4, 5 and 6 m o n t h s very few res is tant cultures were obta ined f rom those cont inuously t r ea t ed wi th s t rep tomycin , whereas a t 4 m on t hs 9 of 15, a t 5 m o n t h s 5 of 9, and at 6 m o n t h s 8 of 9 positive cultures were res is tant to I . N . t t . in the in te rmi t t en t group.

Streptomycin Resistance : At 2 m on t hs 1 of 43 posit ive cultures obta ined f rom 102 pa t ien ts on cont inuous s t r ep tomyc in and I . N . t t . and 2 of 59 positive cul tures f rom 131 pa t ien ts on the in t e rmi t t en t regimen were s t rep tomycin- res is tan t . At 3 m o n t h s no res is tant s t ra in was found in the 22 posit ive cul tures in the cont inuous group and 3 were found among the 31 posit ives in the i r t e r m i t t e n t group. F r o m 7 positive cul- tu res isolated at 4 m o n t h s f rom the cont inuous t r e a t m e n t group only 1 was res i s tan t and no res is tant s t ra in occured in the 3 and 2 positive cul tures at the fifth and s ixth m o n t h s respectively. I n cases receiving in t e rmi t t en t s t rep tomycin , 1 of 14 positive cul tures was res is tant at 4 m o n t h s and again at 5 m o n t h s ; and a t 6 months , 3 of 9 posit ive cultures were resis tant .

On these grounds the Medical Research Council stressed that the use of s treptomycin 1 G. twice weekly and I.N.H. 200 mgm. daily as a pr imary therapeutic measure could not be recommended. Since I.N.H. and thiosemicarbazone mutual ly protect one another it is reasonable to assume that s treptomycin could safely be given intermittently, arguing that the ful ly protected I.N.H. provides total cover for it, as indeed the thiosemi-

T A B L E I I A . Clinical Progress.

Pa t i en t Change in General

Condit ion

E .S .R. (mm. lhr . Westergren

Weight (lb.)

0 m o n t h s 3 - m o n t h s

133 lbs. 145 lbs.

127 136

159 158

129 146

0 M o n t h s 3 Months

:No. 7 T.G. Good 37 8

No. 8 F.C. Good 52 - -

No. 9 P.O.I=t. Very good 54 - -

No. l0 E . R . Very good 4 - -

" T E B A F E N " IN PULMONARY TUBERCULOSIS

T A B L E I I B . Radiological Progress.

81

:Patient Radiologica l .

No. 7 T.G. L . U . L . large t en s i on c a v i t y wi th some s u r r o u n d i n g inf i l t ra t io~ ; R . U . L , inf i l t ra ted t h r o u g h o u t , a m o d e r a t e c a v i t y

No. 8 F .C. L .U .L . h e a v i l y m o t t l e d w i t h probable ax i l l a ry cav i ty . Smal l m i dzone focus ol) R ,

No. 9 :P.O.R. L . U . L . r e a c t i v a t i o n w i t h wide ly dis- t e n d e d c a v i t y a n d an a c u t e sp r ead to t he 1%. a p e x

NO. 10 E . R . L . U . L , i r regular c a v i t y wi th e x t e n s i v e m o t t l i n g ; possible c a v i t y in L. dorsa l s e g m e n t ; c a v i t a t e d con. t r a c t e d a n d m o t t l e d I%.U.L.

Change a t 3 M o n t h s

C a v ~ I-

+2_ +2 §

+ 1 + 3 §

§ + 3 §

+ 2 + 3 + 5

Abbreviations used in the Radiological Tables: l ~ . ~ r i g b t ; L - - l e f t ; U . L . - ~ U p p e r lobe ; LL,----Lower lobe.

Cav i t a t i on (Cav). In f i l t r a t ion (Inf.)

+ 4 = c l o s e d , + 3 ~ r e d u c e d to 1/3. + 4 = c l e a r e d . + 3 - ~ m a r k e d l y r educed .

= 2 = r e d u c c d to �89 + l = r e d u c c d to 2/3. + 2 = c o n s i d e r - able c lear ing + 1 ~ s o m e clearing.

0----no change 0----no change

- - 1 = e n l a r g e d . -- 2 - ~ m a r k e d l y enlarged -- 1 ----local -- 2 de te r io ra t ion a n d de te r io ra t ion sp read .

earbazone does also. The conservation of streptomycin for later use, part icular ly if major thoracic surgery is contemplated, and the reduc- tion of the possibility of ototoxicity are the minor laudable aims of an intermit tent s treptomycin regimen with daily administration of " Tebafen ", such as was carried out in the second par t of this trial.

Mater ia l . All patients included were bacteriologically proven cases of puhnonary

tuberculosis with unequivocal clinical and radiologieal evidence of activity. Pa r t I was conducted on cases showing an acute exacerbation in the course of chronic fibrocavernous disease which (with one exception) had not received antituberculous chemotherapy within the previous year. Only acute newly-discovered cases never previously subjected to treat- ment were admit ted to Par t II .

To the patients in Pa r t I six tablets of " Tebafen " (each containing 10 mgm. nicotinaldehyde/thiosemicarbazone and 40 mgm. I.N.H.) were daily administered for three months. Careful haematological control was observed during this period, af ter which no fur ther chemotherapy was permit ted unti l another three months had elapsed when "f inal " radio- logical assessment was made.

82 I R I S H J O U R N A L OF M E D I C A L S C I E N C E

In Pa r t I I " Tebafen " was s imilar ly administered and in addition 1 G. s t reptomycin was given every th i rd day. Because of the act ivi ty of the tuberculous disease in these pa t ien ts a 3-month t reatment-free period was not observed.

In both groups before and a f t e r chemotherapy the pat ient was weighed �9 ~nd chest x-ray fihns were taken and at monthly intervals urinalysis and erythrocyte sedimentat ion ra te estimations were carried out.

Toxicity. The toxic manifestat ions of I .N.H. intolerance or overdosage are too

well known to need repet i t ion here, but a br ief review of the disturbances sometimes caused by the thiosemicarbazone may be mentioned. Mertens and Bunge ~2 believed tha t m a n y of them were due to overdosage and grouped them as follows: gastr ic irr i tat ion, hepatotoxicity, encephalo- pathy, conjunctivit is and exanthemata , and haematopeietic depression. MerkeP '~ and Pribi l la and Ot ta TM found tha t dosage was a factor in pro- ducing agranulocytosis and anaemia respectively. However, about that t ime Viets and Scholtze ~5 found tha t a dosage as low as 25 mgm. daily sufficed for acute disease, and no adverse effect was noted in intensely observed pat ients (admit tedly a very small number) in Par t I of this t r ial who were receiving 60 mgm. daily.

Resul ts--Part I. Clinical: Table I A shows a very good response. Weight gain averaged

one stone, and lowering of the e ry throcyte sedimentation rate in the major i ty of cases, a l though in one case it more than doubled itself, gave unassailable corroborat ion of the subjective as well as objective improve- ment in the general condition, which was retained three months af ter the cessation of chemotherapy.

Table IB. Serial control examinat ions did not reveal any toxic effect on the haematopoiet ic system. All the pat ients began with ra ther low red cell counts, and in each one a slight rise, which could not be con- sidered other than salutary, occurred. The leucocyte count fell in all cases except one, but never below normal limits.

Radiological: Table IC. Cav i ta ry improvement seemed to be some- what bet ter than the infil trative change. No dramat ic closure or clearing was observed but, f a r more significantly, deterioration was conspicuously absent. I n fact, the t r end of improvement was mainta ined in the three months following chemotherapy when the pa t ien ts were on bed rest alone, thus betokening a more than ephemeral effect. At three months, how- ever, the average overall change was just above + 3.

Bacteriological: Table ID. In one case (No. 4., W.O.D.), a man who had had three months s t reptomycin (1 G) every third day with P.A.S. immediately pr ior to the trial, but who was included mainly because it was believed that his fibroid lesion would continue to produce bacterio- logical evidence, conversion did occur. In another case (No. 1., B.R.) it was not possible to culture bacilli f rom the sputum, although they were in te rmi t ten t ly present in direct smears. Of the four cases in which growth was possible three were ful ly sensitive to I .N.H. and the fourth, (No. 5, E.S.) was resistant. This last pa t ient admit ted to having had I .N.H. alone eighteen months previously, which fact was not elicited

" T E B A F E N " IN P U L M O N A R Y TUBERCULOSI ,~ 83

until the tr ial had terminated. Although this resistant s t ra in was isolated the clinical response was not impaired. Along with improvement in the " parent " lesion in the lef t uppe r lobe, an acute cavitated spread to the r ight lung had almost cleared at six months, while the sedimenta- tim1 rate fell f rom 15 to 4 mm. in 1 hour.

Part II .

This section of the t r ia l was begun on five patients. In one instance chemotherapy was discontinued a f t e r six weeks because of the appearance of an acute confusional psychosis which was considered to have been brought to the surface by one of the drugs. The reaction was f a r too severe to a t tempt by trial and e r ror to find which substance was the actual st imulant , but our impression was tha t I .N.H. was to blame.

Clinical: I IA . One pat ient lost one pound in weight and the remain- ing three gained, but not to the same extent as the pat ients in Pa r t I. Es t imat ion of the erythrocyte sedimentat ion rate unfor tuna te ly could not be carr ied out in the major i ty .

Radiological: I IC. All the pat ients did well, and two did very well with much reduction in cavity size and extent of infiltration. In one (No. 10, E.R.) of these two eases the drugs were administered in the last t r imester of p regnancy and the second radiograph was taken af ter delivery. I t is difficult to measure the exact contr ibution which post- pa r t um lowering of the d iaphragm made to the radiological change - - fo r good or ill. The other (No. 9, P.O.R.), a man of 32 years, received 30 G st reptomycin every second day with P.A.S., I .N.H. alone for 3 weeks, daily s t reptomycin (60 G) with I .N.H. and P.A.S. for 2 months and I .N.H. and P.A.S. for 3 months, but all previous chemotherapy had ended one year pr ior to his inclusion in the present trial. He was at that t ime t reated for an excavated tubereuloma at the left apex, but refused surgical intervention. On this occasion breakdown was accom- panied by pyrexia and spread to the opposite side, which gave rise to a painful dry pleurisy. The average overall change at three months in this group was +4-5, a 50 per cent. improvement on the corresponding figure in Pa r t I.

Bacteriological: I ID . The conversion rate was ra ther too good ; that is lo say, it was bet ter than ant ic ipated and precluded any a t tempt to ascer- tain bacil lary sensitivity.

Disc~ession. The findings of previous workers 7, 8 with these two drugs in combina-

tion are confirmed in Pa r t I of the trial. The clinical and radielogical response was very sat isfactory and the 75 per cent. prevent ion of resist- ance was adequate. The baci l lary resistance encountered in one case did not h inder clinical and radiological progress, so it is reasonable to assume that in this case the total bacterial populat ion was not insensitive to I .N.H.

The difference when s t reptomycin was added to the t reatment pro- g ramme is very apparent . The radiologieal overall result at 3 months improved by 50 per cent. but the 100 per cent. bacteriological conver- sion prevented laboratory measurement of retention of sensitivity or of resistance evolution. The clinico-radiological response certainly favours

84 I R I S H JOURNAL OF MEDICAL S CIEN CE

the hypothesis that bacil lary sensitivity was retained throughout the period of administration.

These results are sufficiently good to warrant fu r ther and larger trials with a view to the wider clinical application of Tebafen. Par t icular ly is this so of its use in combination with intermit tent streptomycin.

Summary. Ten cases of pulmonary tuberculosis have been treated with a com-

bination of I.N.H. and thiosemicarbazone; in four cases streptomycin was administered also at 3-day intervals. The results obtained are suffi- ciently good to indicate the advisability of fu r the r trials.

Acknowledgements. Grateful acknowledgements axe due to Dr. John Duffy, Resident Medical Super-

intendent , for permission to publish and guidance in preparation ; to Miss Joan Hayden Medical Secretary, for her assistance since the inception of tile trial ; and to Dr. W. S. Stoddart of Geigy Pharmaceutical Co., Ltd. for supplies of Tebafen.

References. 1. Joiner, MacLean et al. (1952) Lancet, ii, 843. 2. Medical Research Council (1953) Brit. Med. J., ii, 1005. 3. Domagk, Behnisch et al. (1946~ Naturwissenschaften, ]0, 315. 4. Heilmeyer, L. (1950) Lancet, i, 26~. 5. Ptaszynski, R. and Salvi, A. (1951) Tubercle, 32, 197. 6. Domagk, G. (1950) Amer. Rev. Tuberc., 61, 8. 7. Langer, ( . (1954) Wien. klin. Wschr.. 66, 440. 8. Ruziczka, O. (1954) Ibid., 66, 465. 9. Hirsch. J . (1952) Naturwissenschaften, 39, 525.

10. Conalty M. L. and O'Rrien B. (1955), 4th Commonwealth Health and Tuber. culosis conference Report , Lancet, ii, 32.

l l . Medical Research Council (1955) Brit. Med. J. , i, 435. 12. Mertens, A. and Bunge, R. (1950) Amer. Rev. Tuberc. 61, 20. 13. Merkel, W. (1949) Tuberkulosearzt, 9, 518. 14. Pribilla, W. and Otte, H. (1949) Ibid., 11, 633. 15. Viets, W. anrl Scholtze, I t . (1949} Ibid., 9, 508.