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A trial of calcium 4-benzamidosalicylate in pulmonary tuberculosis
juq
1955
209
A Trial of Calcium 4-Benzamidosalicylate in Pulmonary Tuberculosis By M. O. J. GIBSON Bow Arrow Hospital, Dartford, Kent and M. M. NAGLEY Grove Park Hospital, S.E.12 Introduction Para-aminosalicylic acid (PAS) has been used extensively in the treatment of all forms of tuberculosis since 1948. It possesses undoubted tuberculostatic properties and its chief virtue lies in its ability to delay the emergence of strains of ~IL tuberculosis resistant to Streptomycin or Isoniazid. In order to achieve th.ese results experience has shown that it is necessary to administer PAS at a dosage level which causes some degree of intolerance in m a n y cases. Gastrointestinal symptoms predominate and these symptoms were present it/55 per cent of 112 cases of pulmonary tuberculosis treated for three months with PAS 20 grammes daily ( M e d i c a l Research Council Investigation I948 ) . O f these patients 38 p e r cent had nausea, 33 per cent diarrhoea and 24 per cent vomiting. Tbis discomfort associated with the use of PAS, together with the doubts which were then expressed as to the optimal dose level, prompted the Medical Research Council (i952) to investigate the problem as to whether smaller dose levels would have the same delaying effect on drug resistance, and in this second trial 115 patients were treated for three months with Streptomycin I gramme daily; in addition 42 of them were given 20 grammes PAS a day, 39 given I o grammes and 34 given 5 grammes per day. The incidence of gastro-intestinal trouble was 52 per cent in the group receiving 2o grammes per day, but was much less (12-15 per cent) in the two groups on the lower dose levels. However, Streptomycin sensitivity tests on the cessation oftreatment showed that the 20 grammes daily dose of PAS was superior in delaying the emergence of resistant strains of ~IL
tuberculosis. Higher dose levels of PAS therefore have tended to become t h e rule a n d possibly due to a higher degree of purity and improved methods of a d m i n i s t r a t i o n patients in recent years have shown a slightly better tolerance to the drug, b u t nevertheless this drug in the form in which it is usually administered, i.e. as sodium or calcium salt, still causes gastro-intestinal symptoms and it is our experience that at the level of I8 grammes per day, administered in the form of cachets, 25 per cent o f our cases have some abdominal symptoms, and another 25 per cent are to some lesser extent inconvenienced. We have not found that variations of PAS from the p h a r m a ceutical point of view in enteric-coated granules have appreciably altered this incidence of intolerance. Bavin and.lames (i953) reported detailed pharmacological studies on a new substance -a calcium salt of 4-benzamidosalicylic acid which is an insoluble substance and, perhaps for this reason, as it turned out, was almost tasteless. T h e y found that it was a white powder which is broken down in the body into PAS and benzoic acid liberating 47.6 per cent by weight of para-aminosalicylic acid. Debray (1953) had mentioned the use of sodium benzamidosalicylate in the treatment of renal tuberculosis, and much work has been done in Liverpool by Gow (1953) and by Ross (1953). More recently both these authors have been using calcium benzamidosalicylate in the management of renal tuberculosis (1955). At the end of 1952 we were offered this substance by Smith & Nephew Research Limited for clinical trial, this being the culmination of
210
July
TUBERCLE
our quest for a suitable PAS substitute. The derivative has the following formula:
<-->ooo I OH
] 2
C a 5 H 2 0 ++ Plan and Conduct of the Trial
( z ) Objective We set ourselves three objectives: (t) T o discover whether this substance (hereinafter called B.PAS) supplied to us as 'Therapas' j u d g e d clinically and radiologieally is as effective as PAS. (~) T o discover if it is as active as PAS in delaying the emergence of resistant strains. (3) T o assess the preference of patients for it as opposed to other forms of PAS and the degree of intolerance to it.
(2) The Cases Apart from a few seriously ill patients there was no actual case selection. Our 2o4 patients represent the average run of cases of active pulmonary tuberculosis admitted to our two hospitals and who were regarded as being in need of chemotherapy as basic treatment for their lesions. With one exception children were excluded from the trial (they scarcely ever object to the taste of PAS in solution and scarcely ever suffer any
1955
abdominal troubles). The single exception is Case x3 in Table II. The patients were treated with B.PAS together with either Streptomycin or Isoniazid. The duration of treatment varied from two to four months after which further cultures of sputum or laryngeal swabs were taken and drug sensitivity tests performed of the resultant POsitives. At the beginning of our investigation it was intended tbat the trial course should be of three months' duration b u t it soon became clear on this regime that it was unusual for sputum cultures to remain positive and that no useful information would accrue in a reasonable period of time concerning resistant organisms. One of us (M. O. J. G.) reduced the trial course to two months and it can be seen from Table II how seldom the cultures were still positive after a second two months' course of drugs. Streptomycin was given as i gramme thrice weekly (M. O. J. G.) and t gramme daily by the other (M. M. N.). Isoniazid was administered as xoo mg. thrice daily or 5o rag. five times daily, this being the rough equivalent of 4 mg./kg, for a Io st. patient. The dose of B.PAS varied as may be seen from Table I, b u t most of the patients were treated with 3"5 grammes thrice daily. Results
( I) Clinical amt Radiological Effect Any attempt at a careful comparison before and after treatment of our 0o 4 cases
TABLE I
Cultures positive within prer'ious three months but negative both hnmediately before and after trial drug course
Cultures posith'e immediately before but negati~,e after #ial drug course
~o grammes
6
6
! 8 grammes ~4 grammes
38 o
38 t8
8 ~
x0"5 grammes
39
30
x5
Daily dose of B.PAS
Cultures positive both immediately beforeand after trial drug course. Seusitivity tests performed
As previous column but not possible to perform sem~ivity tests
2 o
S~utum
conversion tale 82 per cent of these 76 positive cases were negative on culture after the trial drug course 67 per cent of these 45 positive cases were negative on culture after trial d r u g course
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w i t h , for instance, the M.R.C. series of patients was felt to be fallacious. There was variation among our cases from those with small non-cavitated lesions of smouldering activity at one end of the scale to those with acute deteriorating bilateral tuberculosis at the other end of the scale. The whole gamut ofpulmonarytuherculous lesions has been run with the exception of the advanced bilateral grossly cavitated disease which would never be fit for any form of thoracic surgery, and on which one could never expect to achieve sputum conversion by drug therapy alone. Table II shows the initial radiological appearances (slight, moderate or extensive) and whether cavitation was demonstrated, by tomography in all instances. Table II gives our results in some detail and it is our general impression that B.PAS in combination with Streptomycin or Isoniazid is neither more nor less effective than PAS. Furthermore, the 84 cases treated with IO. 5 grammes daily appear to have fared just as well as those on I4, x8 or 2I grammes daily.
(2) Sputum Conversion and Drug Sensitivity It will be seen from Table I that 83 patients were sputum culture negative (minimum of three cultures) before the beginning of the trial drug course. All of these had positive cultures at some time, however, during the preceding three months and all were regarded as still having pulmonary tuberculosis requiring treatment at the time that their course was started. All still produced negative cultures after the trial course. The assessment of sputum conversion is that 82 per cent of the positive cases who received i4, x8 or 2I grammes daily of B.PAS were negative after the trial course (i.e. on culture) but of the 45 positive cases who were given io. 5 grammes of B.PAS daily 66 per cent were negative on culture after treatment and we feel that this difference in conversion rate may well be due to the fact that, whereas the average duration of trial treatment for the I4, I8 and 2I
July,
1955
grammes series was 3"8 months, that for the Io. 5 grammes series was n'4 months. Table II shows the drug sensitivity tests performed after the trial on 27 of the 29 patients whose cultures were still positive. 8 of these 27 had previously received chemotherapy, and from 7 of tbese we obtained Streptomycin sensitivity tests on cultures set up immediately before the trial was started, and 6 of these had organisms which were fully sensitive to Streptomycin, but unfortunately their initial sensitivities to PAS and Isoniazid were not obtained. We therefore consider that Cases 2 and 4 in Table II must be excluded from an assessment o f the post-trial sensitivity results of the main drug which was used. Our numbers are too small to give results of any statistical significance but we feel that the results of our sensitivity tests are as good as one would expect had PAS been used instead of B.PAS. O f the 25 cases whose organisms were either known or expected to be sensitive to the main drug used in the trial, o 3 were still fully sensitive after the trial (resistance developed in Case 22 after four months with Streptomycin with B.PAS, and Case 23 showed a doubtful resistance to Isoniazid; neither of these patients had previously received chemotherapy and both were deemed to require thoracic surgery.; both were treated with B.PAS Io. 5 grammes daily). Case 8 should properly be excluded in assessing the post trial PAS sensitivity results. H e had been treated for long periods with Streptomycin and PAS and more recently with Isoniazid and PAS. Before the trial his bacilli were sensitive to Streptomycin, but their response hz vitro to Isoniazid and PAS was not established. After our course of Streptomycin and B.PAS his bacilli were still sensitive to Streptomycin, but moderately resistant to Isoniazid and slightly resistant to PAS. Post-trial PAS sensitivity tests were performed on 2n of the remaining 26 cases and in only 2 of these had any degree of resistance to PAS developed.
July
1955
TUBERCLE
213
It was ascertained either from the patients' (3) Patients' Preference and Tolerance (I) Preference.-46 patients treated pre- own evidence or by filrther small trial that viously with sodium PAS cachets, after only 3 of these I6 B.PAS-intolerant patients several week~' treatment with B.PAS were were devoid of similar symptoms when specifically questioned as to which of these taking PAS. Expressed as percentage of the Ioo patients two preparations they preferred. 39 of the 46 preferred B.PAS and none revised their treated with i8 or 2I grammes of B.PAS opinion in favour of PAS solution o f which per day. I I per cent developed symptoms of they were given a trial. 22 of these 39 pre- intolerance and of the 84 per cent treated t~rred B.PAS because they disliked swallow- with IO. 5 grammes per day 3 per cent ing cachets and detested the bitter taste of developed intolerance. PAS in solution, and the remaining 17 of Discussion these 39 patients suffered from gastroIt is reasonable to assume that these 204 intestinal disturbances while taking PAS patients are representative of adult tuberfrom which they were free or nearly free culous patient~ in general as regards subwhen they took B.PAS. jective and o~,jeetive leactions to chemoNone of the 7 patients who prefer PAS to therapy, and therefore to PAS and B.PAS, B.PAS objected to PAS ill cachet form, nor did they have any symptoms of intolerance. and it appears that approximately 8 per Two of them disliked the taste of B.PAS and cent of any group of adults prefer PAS t o were in favour of PAS as they had no trouble B.PAS, usually because they would rather in 'swallowing cachets. In the remaining 5 swallow cachets than experience the slightly cases B.PAS itself caused nausea, vomiting sweet after-taste of B.PAS, and because and diarrhoea, and 2 of these 5 were very they can be numbered amongst the 5 ° per disturbed but had no trouble with PAS cent or so of people who have no gastrocachets when they were substituted for intestinal symptoms with PAS. The great B.PAS. 5 of our 46 patients received a trial majority, however, (92 per cent in our daily dose of Io'5 grammes and the remain- series) prefer B.PAS to either PAS in ing 41 received x8 or 2I grammes of B.PAS. cachets or solution. This new drug stands or fails by its None of the 5 patients on the lower dose of ability, in comparison with PAS, to delay B.PAS preferred PAS. (2) Tolerance.--A survey of the 204 the emergence of Streptomycin or Isoniazid patients treated in this trial with B.PAS resistant strains of tubercle bacilli. We are showed that only ~6 presented any symp- sensible of the fact that our results as shown toms due to this drug apart from slight in Table II, partly because of the short dislike of the taste when the higher dose duration of I2 of the 27 drug courses, are was given. Such symptoms of intolerance no more than very suggestive of the fact were gastro-intestinal in 14 of the I6. Only that B.PAS is as effective as PAS in this 2 patients in tbis trial developed any skin bacteriological respect. Further trials are now being conducted manifestations and both were urticarial, abolished by antihistamine therapy by by one of us (hi. O . J . G . ) giving a standard mouth which was continued to 'cover' the three months B.PAS course with StreptoB.PAS course; both these patients had mycin or Isoniazid to establish whether this previously developed an urticarial rash daily dose of to" 5 grammes B.PAS is when given PAS in cachet form. 2 of the 16 adequate, and further sensitivity tests will patients who were intolerant to B.PAS be carried out upon any positive cultures were treated with IO'5 grammes daily; one grown immediately after, and then one suffered from nausea alone and the other month after the course, during which month the patients will have no chemotherapy. developed urticaria.
TUBERCLE
214
7 grammes (two powders of 'Therapas') taken as a draught suspended in milk or water leaves a slightly sweet after-taste which some patients m a y dislike, but 3"5 grammes similarly taken is virtually tasteless. A furthcr advantage of the zo- 5 grammes daily dose is one of economy. It will be seen that io of the 15 patients who receive Io. 5 grammes only were treated for only two months. I n the M.R.C. trial (I952) where different doses of PAS were tried with Streptomycin, it was found that at the end of three months' treatment on Streptomycin with either zo or 20 grammes PAS per day, the Streptomycin sensitivity results were satisfactory. Resistant strains presented in 8 per cent of the zo grammes daily, and 4 per cent of the 20 grammes daily groups, but subsequently the figure remains low for the higher dose but high for the lower dose. In the fourth month the proportion of resistant cases was 43 per cent for the I0 grammes and z5 per cent for the 2o grammes group. In the sixth month the corresponding figures were 3 ° per cent and 7 per cent. Therefore our satisfactory sensitivity results at the end of two months' treatment are merely a lead and cannot be regarded with equanimity.
Summary (I) A clinical trial has been carried out with Calcium 4-Benzamidosalieylate in 2o 4 cases of pulmonary tuberculosis in order to try- to determine its place in the armamentarium of anti-tuberculous drugs. (2) Most patients prefer the drug to other forms of PAS, particularly PAS in solution and in cachets because of the reduction in gastro-intestinal disturbances. (3) It is our impression that Calcium 4-Benzamidosalicylate is equally effective, as judged by treatment of hospital inpatients, as PAS and this should be quickly confirmed. (4) Results produced from the bacteriological viewpoint showed sputum conversion in all but 29 of the 2o 4 cases and sensitivity tests reported on 27 of these cases suggest
Juq:1955
that the new substance might well be as effective as PAS in delaying the emergence of strains resistant to Streptomycin. (5) It would seem that Calcium 4Benzamidosalicylate at a dosage level o f I4 grammes per day or more could well replace the standard dosage level of Sodium PAS in cachets or in solution with much relief to the patient.
Acknowledgments It gives us great pleasure to acknowledge our indebtedness to Messrs Smith & Nephew Research Ltd., of Hunsdon, Herts, who supplied us with 'Therapas' for this trial, to Dr E. Bailey of the Southern Group Laboratories and Dr H. G. Close of the Dartford Group Laboratories for the culture and sensitivity work, and to the Medical and Nursing Staffs of the two hospitals who cared for these patients. References
Bavln, E. M., and James, B. 0953) ffourn. Pharm. et. Pharmicol, v. 849. Debray, J. R. (t953) Presse Med., LYre, 647. Gow, J. G. (I953) Brit. 3Ied. ffourn., x, 95. Medical Research Council Investigation (I948) Brit. Med. ~7ourn., It, 769 . Medical Research Council Investigation (z952) Brit. Med. .~ourn.~ I~ I I57. Ross, J. C. '0953) Proc. Roy. Soc. 3[ed., xuw, 434. Ross, J. C., Gow, J. G., and St. Hill, C. A. (z953) Brlt. 3Ied. ~7ourn. I, 9oi. Ross, J. C., Gow, J. G., and St. Hill, C. A. (z955) Lancet, r, zi6.
NOTICE TO CONTRIBUTORS Contributions are invited from authoritative sources on the understanding customary to medical publications. h is requested that articles should, if possible, be restricted t o between 3,000 and 4,000 words, and only in
exceptional circumstances will articles over 5,000 words be published. This rule is necessitated by the paper rationing and by the fact that we still have space for less than half of the papers submitted, Contributors are asked to state the approximate number of words at the end of the article. Opinions put forward in this Journal, unless expressly ;:ostated, do not necessarily represent the policy of the British Tuberculosis Association.
1955
209
A Trial of Calcium 4-Benzamidosalicylate in Pulmonary Tuberculosis By M. O. J. GIBSON Bow Arrow Hospital, Dartford, Kent and M. M. NAGLEY Grove Park Hospital, S.E.12 Introduction Para-aminosalicylic acid (PAS) has been used extensively in the treatment of all forms of tuberculosis since 1948. It possesses undoubted tuberculostatic properties and its chief virtue lies in its ability to delay the emergence of strains of ~IL tuberculosis resistant to Streptomycin or Isoniazid. In order to achieve th.ese results experience has shown that it is necessary to administer PAS at a dosage level which causes some degree of intolerance in m a n y cases. Gastrointestinal symptoms predominate and these symptoms were present it/55 per cent of 112 cases of pulmonary tuberculosis treated for three months with PAS 20 grammes daily ( M e d i c a l Research Council Investigation I948 ) . O f these patients 38 p e r cent had nausea, 33 per cent diarrhoea and 24 per cent vomiting. Tbis discomfort associated with the use of PAS, together with the doubts which were then expressed as to the optimal dose level, prompted the Medical Research Council (i952) to investigate the problem as to whether smaller dose levels would have the same delaying effect on drug resistance, and in this second trial 115 patients were treated for three months with Streptomycin I gramme daily; in addition 42 of them were given 20 grammes PAS a day, 39 given I o grammes and 34 given 5 grammes per day. The incidence of gastro-intestinal trouble was 52 per cent in the group receiving 2o grammes per day, but was much less (12-15 per cent) in the two groups on the lower dose levels. However, Streptomycin sensitivity tests on the cessation oftreatment showed that the 20 grammes daily dose of PAS was superior in delaying the emergence of resistant strains of ~IL
tuberculosis. Higher dose levels of PAS therefore have tended to become t h e rule a n d possibly due to a higher degree of purity and improved methods of a d m i n i s t r a t i o n patients in recent years have shown a slightly better tolerance to the drug, b u t nevertheless this drug in the form in which it is usually administered, i.e. as sodium or calcium salt, still causes gastro-intestinal symptoms and it is our experience that at the level of I8 grammes per day, administered in the form of cachets, 25 per cent o f our cases have some abdominal symptoms, and another 25 per cent are to some lesser extent inconvenienced. We have not found that variations of PAS from the p h a r m a ceutical point of view in enteric-coated granules have appreciably altered this incidence of intolerance. Bavin and.lames (i953) reported detailed pharmacological studies on a new substance -a calcium salt of 4-benzamidosalicylic acid which is an insoluble substance and, perhaps for this reason, as it turned out, was almost tasteless. T h e y found that it was a white powder which is broken down in the body into PAS and benzoic acid liberating 47.6 per cent by weight of para-aminosalicylic acid. Debray (1953) had mentioned the use of sodium benzamidosalicylate in the treatment of renal tuberculosis, and much work has been done in Liverpool by Gow (1953) and by Ross (1953). More recently both these authors have been using calcium benzamidosalicylate in the management of renal tuberculosis (1955). At the end of 1952 we were offered this substance by Smith & Nephew Research Limited for clinical trial, this being the culmination of
210
July
TUBERCLE
our quest for a suitable PAS substitute. The derivative has the following formula:
<-->ooo I OH
] 2
C a 5 H 2 0 ++ Plan and Conduct of the Trial
( z ) Objective We set ourselves three objectives: (t) T o discover whether this substance (hereinafter called B.PAS) supplied to us as 'Therapas' j u d g e d clinically and radiologieally is as effective as PAS. (~) T o discover if it is as active as PAS in delaying the emergence of resistant strains. (3) T o assess the preference of patients for it as opposed to other forms of PAS and the degree of intolerance to it.
(2) The Cases Apart from a few seriously ill patients there was no actual case selection. Our 2o4 patients represent the average run of cases of active pulmonary tuberculosis admitted to our two hospitals and who were regarded as being in need of chemotherapy as basic treatment for their lesions. With one exception children were excluded from the trial (they scarcely ever object to the taste of PAS in solution and scarcely ever suffer any
1955
abdominal troubles). The single exception is Case x3 in Table II. The patients were treated with B.PAS together with either Streptomycin or Isoniazid. The duration of treatment varied from two to four months after which further cultures of sputum or laryngeal swabs were taken and drug sensitivity tests performed of the resultant POsitives. At the beginning of our investigation it was intended tbat the trial course should be of three months' duration b u t it soon became clear on this regime that it was unusual for sputum cultures to remain positive and that no useful information would accrue in a reasonable period of time concerning resistant organisms. One of us (M. O. J. G.) reduced the trial course to two months and it can be seen from Table II how seldom the cultures were still positive after a second two months' course of drugs. Streptomycin was given as i gramme thrice weekly (M. O. J. G.) and t gramme daily by the other (M. M. N.). Isoniazid was administered as xoo mg. thrice daily or 5o rag. five times daily, this being the rough equivalent of 4 mg./kg, for a Io st. patient. The dose of B.PAS varied as may be seen from Table I, b u t most of the patients were treated with 3"5 grammes thrice daily. Results
( I) Clinical amt Radiological Effect Any attempt at a careful comparison before and after treatment of our 0o 4 cases
TABLE I
Cultures positive within prer'ious three months but negative both hnmediately before and after trial drug course
Cultures posith'e immediately before but negati~,e after #ial drug course
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6
6
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38 o
38 t8
8 ~
x0"5 grammes
39
30
x5
Daily dose of B.PAS
Cultures positive both immediately beforeand after trial drug course. Seusitivity tests performed
As previous column but not possible to perform sem~ivity tests
2 o
S~utum
conversion tale 82 per cent of these 76 positive cases were negative on culture after the trial drug course 67 per cent of these 45 positive cases were negative on culture after trial d r u g course
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1955
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w i t h , for instance, the M.R.C. series of patients was felt to be fallacious. There was variation among our cases from those with small non-cavitated lesions of smouldering activity at one end of the scale to those with acute deteriorating bilateral tuberculosis at the other end of the scale. The whole gamut ofpulmonarytuherculous lesions has been run with the exception of the advanced bilateral grossly cavitated disease which would never be fit for any form of thoracic surgery, and on which one could never expect to achieve sputum conversion by drug therapy alone. Table II shows the initial radiological appearances (slight, moderate or extensive) and whether cavitation was demonstrated, by tomography in all instances. Table II gives our results in some detail and it is our general impression that B.PAS in combination with Streptomycin or Isoniazid is neither more nor less effective than PAS. Furthermore, the 84 cases treated with IO. 5 grammes daily appear to have fared just as well as those on I4, x8 or 2I grammes daily.
(2) Sputum Conversion and Drug Sensitivity It will be seen from Table I that 83 patients were sputum culture negative (minimum of three cultures) before the beginning of the trial drug course. All of these had positive cultures at some time, however, during the preceding three months and all were regarded as still having pulmonary tuberculosis requiring treatment at the time that their course was started. All still produced negative cultures after the trial course. The assessment of sputum conversion is that 82 per cent of the positive cases who received i4, x8 or 2I grammes daily of B.PAS were negative after the trial course (i.e. on culture) but of the 45 positive cases who were given io. 5 grammes of B.PAS daily 66 per cent were negative on culture after treatment and we feel that this difference in conversion rate may well be due to the fact that, whereas the average duration of trial treatment for the I4, I8 and 2I
July,
1955
grammes series was 3"8 months, that for the Io. 5 grammes series was n'4 months. Table II shows the drug sensitivity tests performed after the trial on 27 of the 29 patients whose cultures were still positive. 8 of these 27 had previously received chemotherapy, and from 7 of tbese we obtained Streptomycin sensitivity tests on cultures set up immediately before the trial was started, and 6 of these had organisms which were fully sensitive to Streptomycin, but unfortunately their initial sensitivities to PAS and Isoniazid were not obtained. We therefore consider that Cases 2 and 4 in Table II must be excluded from an assessment o f the post-trial sensitivity results of the main drug which was used. Our numbers are too small to give results of any statistical significance but we feel that the results of our sensitivity tests are as good as one would expect had PAS been used instead of B.PAS. O f the 25 cases whose organisms were either known or expected to be sensitive to the main drug used in the trial, o 3 were still fully sensitive after the trial (resistance developed in Case 22 after four months with Streptomycin with B.PAS, and Case 23 showed a doubtful resistance to Isoniazid; neither of these patients had previously received chemotherapy and both were deemed to require thoracic surgery.; both were treated with B.PAS Io. 5 grammes daily). Case 8 should properly be excluded in assessing the post trial PAS sensitivity results. H e had been treated for long periods with Streptomycin and PAS and more recently with Isoniazid and PAS. Before the trial his bacilli were sensitive to Streptomycin, but their response hz vitro to Isoniazid and PAS was not established. After our course of Streptomycin and B.PAS his bacilli were still sensitive to Streptomycin, but moderately resistant to Isoniazid and slightly resistant to PAS. Post-trial PAS sensitivity tests were performed on 2n of the remaining 26 cases and in only 2 of these had any degree of resistance to PAS developed.
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It was ascertained either from the patients' (3) Patients' Preference and Tolerance (I) Preference.-46 patients treated pre- own evidence or by filrther small trial that viously with sodium PAS cachets, after only 3 of these I6 B.PAS-intolerant patients several week~' treatment with B.PAS were were devoid of similar symptoms when specifically questioned as to which of these taking PAS. Expressed as percentage of the Ioo patients two preparations they preferred. 39 of the 46 preferred B.PAS and none revised their treated with i8 or 2I grammes of B.PAS opinion in favour of PAS solution o f which per day. I I per cent developed symptoms of they were given a trial. 22 of these 39 pre- intolerance and of the 84 per cent treated t~rred B.PAS because they disliked swallow- with IO. 5 grammes per day 3 per cent ing cachets and detested the bitter taste of developed intolerance. PAS in solution, and the remaining 17 of Discussion these 39 patients suffered from gastroIt is reasonable to assume that these 204 intestinal disturbances while taking PAS patients are representative of adult tuberfrom which they were free or nearly free culous patient~ in general as regards subwhen they took B.PAS. jective and o~,jeetive leactions to chemoNone of the 7 patients who prefer PAS to therapy, and therefore to PAS and B.PAS, B.PAS objected to PAS ill cachet form, nor did they have any symptoms of intolerance. and it appears that approximately 8 per Two of them disliked the taste of B.PAS and cent of any group of adults prefer PAS t o were in favour of PAS as they had no trouble B.PAS, usually because they would rather in 'swallowing cachets. In the remaining 5 swallow cachets than experience the slightly cases B.PAS itself caused nausea, vomiting sweet after-taste of B.PAS, and because and diarrhoea, and 2 of these 5 were very they can be numbered amongst the 5 ° per disturbed but had no trouble with PAS cent or so of people who have no gastrocachets when they were substituted for intestinal symptoms with PAS. The great B.PAS. 5 of our 46 patients received a trial majority, however, (92 per cent in our daily dose of Io'5 grammes and the remain- series) prefer B.PAS to either PAS in ing 41 received x8 or 2I grammes of B.PAS. cachets or solution. This new drug stands or fails by its None of the 5 patients on the lower dose of ability, in comparison with PAS, to delay B.PAS preferred PAS. (2) Tolerance.--A survey of the 204 the emergence of Streptomycin or Isoniazid patients treated in this trial with B.PAS resistant strains of tubercle bacilli. We are showed that only ~6 presented any symp- sensible of the fact that our results as shown toms due to this drug apart from slight in Table II, partly because of the short dislike of the taste when the higher dose duration of I2 of the 27 drug courses, are was given. Such symptoms of intolerance no more than very suggestive of the fact were gastro-intestinal in 14 of the I6. Only that B.PAS is as effective as PAS in this 2 patients in tbis trial developed any skin bacteriological respect. Further trials are now being conducted manifestations and both were urticarial, abolished by antihistamine therapy by by one of us (hi. O . J . G . ) giving a standard mouth which was continued to 'cover' the three months B.PAS course with StreptoB.PAS course; both these patients had mycin or Isoniazid to establish whether this previously developed an urticarial rash daily dose of to" 5 grammes B.PAS is when given PAS in cachet form. 2 of the 16 adequate, and further sensitivity tests will patients who were intolerant to B.PAS be carried out upon any positive cultures were treated with IO'5 grammes daily; one grown immediately after, and then one suffered from nausea alone and the other month after the course, during which month the patients will have no chemotherapy. developed urticaria.
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7 grammes (two powders of 'Therapas') taken as a draught suspended in milk or water leaves a slightly sweet after-taste which some patients m a y dislike, but 3"5 grammes similarly taken is virtually tasteless. A furthcr advantage of the zo- 5 grammes daily dose is one of economy. It will be seen that io of the 15 patients who receive Io. 5 grammes only were treated for only two months. I n the M.R.C. trial (I952) where different doses of PAS were tried with Streptomycin, it was found that at the end of three months' treatment on Streptomycin with either zo or 20 grammes PAS per day, the Streptomycin sensitivity results were satisfactory. Resistant strains presented in 8 per cent of the zo grammes daily, and 4 per cent of the 20 grammes daily groups, but subsequently the figure remains low for the higher dose but high for the lower dose. In the fourth month the proportion of resistant cases was 43 per cent for the I0 grammes and z5 per cent for the 2o grammes group. In the sixth month the corresponding figures were 3 ° per cent and 7 per cent. Therefore our satisfactory sensitivity results at the end of two months' treatment are merely a lead and cannot be regarded with equanimity.
Summary (I) A clinical trial has been carried out with Calcium 4-Benzamidosalieylate in 2o 4 cases of pulmonary tuberculosis in order to try- to determine its place in the armamentarium of anti-tuberculous drugs. (2) Most patients prefer the drug to other forms of PAS, particularly PAS in solution and in cachets because of the reduction in gastro-intestinal disturbances. (3) It is our impression that Calcium 4-Benzamidosalicylate is equally effective, as judged by treatment of hospital inpatients, as PAS and this should be quickly confirmed. (4) Results produced from the bacteriological viewpoint showed sputum conversion in all but 29 of the 2o 4 cases and sensitivity tests reported on 27 of these cases suggest
Juq:1955
that the new substance might well be as effective as PAS in delaying the emergence of strains resistant to Streptomycin. (5) It would seem that Calcium 4Benzamidosalicylate at a dosage level o f I4 grammes per day or more could well replace the standard dosage level of Sodium PAS in cachets or in solution with much relief to the patient.
Acknowledgments It gives us great pleasure to acknowledge our indebtedness to Messrs Smith & Nephew Research Ltd., of Hunsdon, Herts, who supplied us with 'Therapas' for this trial, to Dr E. Bailey of the Southern Group Laboratories and Dr H. G. Close of the Dartford Group Laboratories for the culture and sensitivity work, and to the Medical and Nursing Staffs of the two hospitals who cared for these patients. References
Bavln, E. M., and James, B. 0953) ffourn. Pharm. et. Pharmicol, v. 849. Debray, J. R. (t953) Presse Med., LYre, 647. Gow, J. G. (I953) Brit. 3Ied. ffourn., x, 95. Medical Research Council Investigation (I948) Brit. Med. ~7ourn., It, 769 . Medical Research Council Investigation (z952) Brit. Med. .~ourn.~ I~ I I57. Ross, J. C. '0953) Proc. Roy. Soc. 3[ed., xuw, 434. Ross, J. C., Gow, J. G., and St. Hill, C. A. (z953) Brlt. 3Ied. ~7ourn. I, 9oi. Ross, J. C., Gow, J. G., and St. Hill, C. A. (z955) Lancet, r, zi6.
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