A second international co-operative investigation into thioacetazone side-effects*

Bull. Org. nmond.Santd 1970, 43, 107-125Bull. Wid Hitha Org. A Second International Co-operative Investigation into Thioacetazone Side-effects* 1. The Influence of a Vitamin and Antihistamine Supplement A. B. MILLER, A. J. NUNN, D. K. ROBINSON, G. C. FERGUSON, WALLACE FOX & RUTH TALL On Behalf of the Co-operating Physicians and Agencies' As part of a large-scale international, co-operative investigation into the side-effects produced by thioacetazone employed in the treatment of tuberculosis, an evaluation has been made ofa supplement incorporating vitamins and an antihistamine as a prophylactic. Over a 12-week period oftreatment, the additive supplementfailed to reduce the over-all frequency of side-effects or the frequency of side-effects leading to a major departurefrom prescribed treatment. There was also no evidence that the more serious side-effects, particularly rashes, jaundice and agranulocytosis, were reduced by the additives, although the occurrence of vomiting, which was however infrequent, was reduced. In view of this lack of appreciable benefit, as well as the higher cost and impaired keeping properties of tablets containing thioacetazone plus isoniazid when the supplement is added, the use of the supplement as a prophylactic cannot be recommended. The use of thioacetazone, an inexpensive drug, was investigated during the course of a series of studies in East Africa designed to find a suitable companion drug for isoniazid in the treatment of tuberculosis. Thioacetazone (150 mg) with isoniazid (300 mg) given in a single dose was found to be an effective regimen with a low level of side-effects (East African/British Medical Research Council Second Thiacetazone Investigation, 1963). As a result, the regimen has been established for several years in many developing countries as an effective combination for the treatment of patients with newly diagnosed pulmonary tuberculosis. Neverthe- less, although the level of side-effects is, in general, acceptable in the socio-economic circumstances in which therapy is undertaken in developing countries, there is evidence of variation in the frequency of side-effects from area to area. In view of this, a careful study of side-effects should always be under- * From the Medical Research Council of Great Britain, Tuberculosis and Chest Diseases Unit, Brompton Hospital, London, England. 1 See Acknowledgements. taken before thioacetazone is introduced into routine practice in a country for the first time (WHO Expert Committee on Tuberculosis, 1964; Miller, Fox & Tall, 1966). The first International Co-operative Thiacetazone Side-Effect Investigation (Miller, Fox & Tall, 1966) indicated that it was desirable to investigate the frequency of side-effects to thioacetazone in a number of other centres, with particular reference to possible variations in the Indian subcontinent and also in centres where different racial groups were under treatment in the same hospitals, in order to help elucidate the reasons for geographical dif- ferences. It has been claimed that an additive supplement to the standard combination of thioacetazone plus isoniazid consisting of vitamins and an antihistamine reduces the frequency of side-effects (Patel, Patel & Mehta, 1965) and the supplement is now widely used as a prophylactic in some parts of Asia. Such a supplement, if really effective, would be valuable, particularly for use in countries which at present encounter a high frequency of side-effects. 2547 - 107- A. B. MILLER AND OTHERS In the present study, a supplement, containing the same quantities of vitamins and antihistamines as those widely used, was investigated as a prophylactic, not only with the basic regimen of thioacetazone plus isoniazid but also with the regimen of thio- acetazone plus isoniazid plus streptomycin, because this is commonly used in the initial intensive phase of chemotherapy (East African/British Medical Research Council Third Thiacetazone Investigation, 1966). The influence of the additives is considered in the present report. In a subsequent report, the geographical distribution of thioacetazone side- effects and the possible influence of race will be considered. The details of cutaneous side-effects will also be reported separately. PLAN AND CONDUCT OF THE INVESTIGATION The investigation was planned and co-ordinated by the Medical Research Council of Great Britain, Tuberculosis and Chest Diseases Unit (TCDU). The investigation was largely organized by cor- respondence since it was not possible to visit most of the centres. Drug regimens Every patient received combined chemotherapy with either two or three antituberculosis drugs. The oral medicaments in each regimen were com- bined in a single tablet, to be taken each morning under direct supervision. All the tablets were specially made for the investigation and were similar TABLE 1 REGIMENS USED IN THE CO-OPERATIVE INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS Oral medicament (tablet) Daily External coat Regimen strepto- mycin (g) Thioaceta- Isoniazid Core zone (mg) (m THA _ 150 300 Additive TH - 150 300 Placebo STHA 1 150 300 Additive STH 1 150 300 Placebo SHA 1 _ 300 Additive SH 1 300 Placebo in appearance and taste. Each consisted of an off- white external coat and a yellow core. The coat contained thioacetazone plus isoniazid or isoniazid alone, and the core contained the additive supple- ment or the placebo. The regimens, shown in Table 1, were allocated at random. The external coats of the tablets were formulated as follows: Thloacetazone plus Isonlazid Thioacetazone 150 mg Isoniazid 300 mg Excipient to 550 mg Isonlazid alone Isoniazid Lactose Colouring as required and excipient to 300 mg 150 mg 550 mg The cores ofthe tablets were formulated as follows: Aditves Buclizine hydrochloride Aneurine hydrochloride Riboflavine Pyridoxine hydrochloride Nicotinic acid Calciferol Excipient to Placebo Lactose Colouring as required and excipient to 12mg 4 mg 4 mg 6 mg 40mg 600 IU 150 mg 106 mg 150 mg It was emphasized to participants in the investiga- tion that it was very important not to prescribe additional vitamins or mineral supplements, and always to record if antihistamines and other drugs were given. Double-blind assessments were made of the regimens so that neither the patient nor the physician in charge knew whether the oral medicament pre- scribed contained the additive or placebo and, for the regimens containing streptomycin, whether thioacetazone plus isoniazid or isoniazid alone was being given. In addition, the co-ordinator in the TCDU recorded the results, coded the side-effects and corresponded with the centres concerning side- effects, also without knowing the nature of the oral medicament. The investigation was, however, closely supervised by two physicians and a statistician in the TCDU, especially in relation to deaths from any cause or to reports of serious side-effects. The oral medicaments for each patient for the full period of the investigation were packed as indi- 108 SECOND INTERNATIONAL INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS. 1 vidual supplies. The containers (tins) of medicament were numbered in a serial sequence corresponding to a random order of the four oral medicaments and were then sent in batches by air-freight to the centres. On two occasions, medicament stored for 12 months at participating centres in the tropics was returned to the United Kingdom for analysis; it was con- firmed that potency had been maintained. (How- ever, the same medicament deliberately allowed to remain in store for more than 12-18 months was found to deteriorate in tropical conditions. In particular, the vitamin content of the tablets with additives fell and, in conditions of high humidity, the isoniazid content also fell.) Duration of chemotherapy Although the prescribed duration ofchemotherapy was 12 weeks, a 16-week supply was provided for every patient. Whenever side-effects were still pre- sent at 12 weeks, reports were continued until the side-effects ceased. Selection ofpatients The investigation was restricted to patients aged 15 years or over with active pulmonary tuberculosis who had had either no previous antituberculosis chemotherapy or chemotherapy for less than 2 weeks but not including treatment with thioacetazone or any other thiosemicarbazone preparation and who were considered to be co-operative and likely to remain in hospital for 12 weeks. Patients were ineligible if they were in very poor general condition, weighed less than 70 lb (32 kg), had a haemoglobin level of less than 6 g/100 ml, were known to be pregnant or had non-tuberculous disease which might contra-indicate either the use of thioacetazone (for example, advanced liver disease) or injections of streptomycin (for example, advanced nephritis). Allocation to treatment Each centre was supplied with a register with serial numbers already entered in sequence. The two containers of oral medicament corresponding to the serial number obtained from the register held the patient's supply of tablets for the investigation. In addition, sealed blue envelopes were supplied bear- ing a serial number corresponding to one of the numbers in the patient register and containing a treatment slip stating whether or not streptomycin was allocated. To admit a patient to the investiga- tion, the details were entered in the register on the next available line, thus allocating the oral medica. ment; the corresponding sealed blue envelope was then opened to see if streptomycin was also allocated. It was emphasized that great care was to be taken to ensure that the patient received oral medicament only from the containers bearing his serial number. Pretreatment investigations The investigation of the patients conformed to the normal practice in the centre and the protocol requests were kept to a minimum. The investigations carried out in all centres were a haemoglobin estima- tion, a total and differential white-cell count and a urine test for protein and sugar. Investigations during treatment In most centres, the only investigation required during treatment was a urine test for protein and sugar at 12 weeks. In centres with more laboratory facilities, a haemoglobin estimation and white- cell and differential counts were also carried out at 4, 8 and 12 weeks. If side-effects occurred, it was recommended that appropriate investigations should be undertaken. Record of side-effects A daily record was kept of any complaint which might indicate side-effects. It was emphasized that patients should not be specially interrogated to elicit symptoms but that each patient was to be seen daily and asked the following standard questions: (1) How do you feel? (2) Have you any cough? These standard questions gave each patient an opportunity to report symptoms every day. Full details of possible side-effects were reported on a special form which had space for a daily record for 2 weeks. In this space was recorded for each day whether possible side-effects had occurred and, if so, the terms shown below were to be used, as far as possible. Group Gastric Cutaneous Symptom 1. Nausea, abdominal discomfort, in- cluding anorexia 2. Vomiting 3. Diarrhoea 4. Constipation 5. Jaundice or hepatitis 1. Flushing, itching, including pruritis, conjunctivitis 2. Rash, including erythema, urticaria 8 109 A. B. MILLER AND OTHERS Group Symptom Vestibular 1. Dizziness, giddiness (if no sense of rotation present 2. Vertigo (if sense of rotation present) 3. Ataxia 4. Tinnitus 5. Deafness Neurological 1. Headache 2. Drowsiness 3. Blurred vision 4. Numbness around mouth 5. Mental symptoms 6. Peripheral nerve symptoms, includ- ing neuritis Haematological Miscellaneous 1. Agranulocytosis 2. Leucopenia 3. Anaemia Other possible side-effects, including fever. The severity of each symptom and details of the clinical action taken were recorded daily; desensitiza- tion procedures were reported on a separate form. Tablets of isoniazid (50 mg) and of thioacetazone (25 mg) were supplied to each centre for tests of hypersensitivity and for desensitization courses. Change ofchemotherapy In order that the physician should be able to learn the composition of a patient's oral medica- ment if the patient developed severe side-effects, each centre was provided with a series of sealed white envelopes, each bearing a serial number and con- taining a slip stating the composition of the oral medicament for the patient with the same serial number. The envelopes were kept by a member of the administrative staff and when an envelope was opened the TCDU was informed by airmail. At the end ofthe study, all the envelopes were returned to the TCDU from all except one of the centres. In the event, envelopes were opened, because of the occur- rence of side-effects, for 10 (0.2%) of the 4075 patients for whom envelopes were returned. Continuation chemotherapy At the end of the 12-week period of treatment, an airmail letter giving the content of the patient's oral medicament was sent to the physician, who was then free to give whatever continuation chemotherapy he wished. Definition ofcertain terms used in this report Side-effect. Any symptom or sign regarded by the physician as being due to chemotherapy. Treatment not interrupted. The regimen was given daily, as prescribed or in reduced dosage. Treatment interrupted. Treatment with streptomy- cin or the oral medicament, or both, was interrupted for 1 or more days on account of a side-effect, but was resumed before the end of the 12-week period. A desensitization course to one or more of the drugs has also been regarded as an interruption. Treatment stopped. Treatment with either strepto- mycin or the oral medicament, or both, was stopped on account of side-effects and not resumed before the end of the 12-week period of study. Major departurefrom prescribed treatment. Treat- ment either stopped or interrupted for 7 days or more on account of side-effects. RESULTS Population admitted A total of 4210 patients were admitted to the investigation from 25 hospitals in 10 countries (Table 2). Patients were allocated to all 6 regimens in all the countries except Czechoslovakia and Morocco, where they were only allocated to the streptomycin- containing regimens. Thus, 621 patients were allo- cated to the THA regimen, 628 to the TH, 742 to the STHA, 733 to the STH, 736 to the SHA and 750 to the SH regimen. TABLE 2 PATIENTS ADMITTED TO, AND NUMBERS EXCLUDED FROM, CO-OPERATIVE INVESTIGATION No of No. of Exclusions No. re-Country hopitl patients mainingh_os ta s admitted No.| % for analysis Algeria 1 368 21 5.7 347 Czechoslovakia 2 204 1 0.5 203 Ethiopia 1 179 4 2.2 175 India 11 1809 142 7.8 1 667 Mailaysia 1 303 6 2.0 297 Mongolia 1 140 2 1.4 138 Morocco 2 178 21 11.8 157 Pakistan 4 442 28 6.3 414 Singapore 1 452 6 1.3 446 Trinidad 1 135 11 8.1 124 All countries 25 - 4210 242 5.7 f 3968 110 SECOND INTERNATIONAL INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS. 1 Exclusions In all, 242 (5.7%Y.) of the 4210 patients allocated were excluded from the analysis, the proportions ranging from 0.5% in Czechoslovakia to 11.8% in Morocco (Table 2). Similar proportions were excluded from each regimen-namely, 6.0% of the THA, 7.5% of the TH, 4.7% of the STHA, 6.0% of the STH, 5.4% of the SHA and 5.2% of the SH patients. The reasons for exclusions are shown in the following tabulation: and SH regimens on the other. This is, first, because when streptomycin was not allocated the physician knew that the patient was receiving a thioacetazone- containing (THA or TH) regimen and, secondly, because in Czechoslovakia and Morocco patients were not allocated to the THA or TH regimens. THE INFLUENCE OF ADDITIVES ON SIDE-EFFECTS TO THE THIOACETAZONE PLUS ISONIAZID REGIMEN Reason for exclusion No. excluded Pretreatment comparisons Weight less than 70 lb (32 kg) 25 There was a preponderance of males in every Previous thioacetazone treatment 168 country except Mongolia, where 46% of 46 patients Treatment changed on account of: were male (Table 3). In all countries except Trinidad, Extr-pulonar tubercuthe majority of patients were aged less than 45 years;Extra-pulmonary tuberculosa s 3 in Trinidad, the proportion of patients aged 45 years Pregnancy 2 or more was 53 % of 43 while, at the other extreme, Pretreatment drugresistance the proportion was 2% of 59 in Ethiopia. The Non-tuberculous disease 4 lightest patients were in India, their average weight Errors in prescribing 12 being 41.2 kg; the heaviest, with an average weight of Incomplete records 6 52.2 kg, were in Trinidad. There was, however, Total exclusions 242 little difference between the regimens within each country (the findings are not tabulated here) and therefore all the patients on the THA regimen have Of the 242 patients excluded, 168 had absconded been amalgamated for comparison with all the from treatment. It is unlikely that side-effects to patients on the TH regimen. The distributions of sex, thioacetazone were specially responsible for patients age, haemoglobin level and weight were all very absconding since the proportions were similar in the similar (Table 3, last columns). regimens and as side-effects were no more common in the absconders than in the patients who remained. Deaths It should be noted, however, that 1 (THA) patient Dunn the 12-week riod 10 5 THA 5 TH absconded in the sixth week while suffering from a pating ie 9 pe(5 THA, 5 H) severe rash and jaundice and died in the seventh patients died, 9 (5 THA, 4 TH) of tuberculosis and week. 1 (TH) of agranulocytosis.week. ~ * Considering the deaths from tuberculosis, only IAfter the exclusions, 3968 patients remained for Consieng the deathsifrom tubercul analysis, 584 on the THA regimen, 581 on the T (T) patient, who died i the sixth week of tubercu- 707 on the STHA, 689 on the STH, 696 on the SHA lous toxaemia, had severe side-effects-namely, and 711 on the SH regimen. stomatitis and mental symptoms. Although the treatment was interrupted it was resumed before Presentation of results death.The TH patient who died of agranulocytosis in the The results are presented in two sections, the first seventh week developed a perianal abscess and dealing with the influence of additives on side- dehydration in the fifth week. His condition dete- effects to the thioacetazone plus isoniazid regimen, riorated in spite of penicillin treatment and rehydra- and the second with the influence of additives on side- tion. No sore throat occurred. Agranulocytosis was effects to the streptomycin plus thioacetazone plus diagnosed on the day of death when there was a isoniazid regimen and on the streptomycin plus total white-cell count of 3200, consisting only of isoniazid regimen. lymphocytes. A bone-marrow specimen obtained A direct comparison cannot be made of the fre- post mortem showed acellular marrow with lympho- quency of side-effects between the THA and theTH cytes and normoblasts only. The study tablets had regimens on the one hand and the STHA, STH, SHA been continued throughout. III A. B. MILLER AND OTHERS _ C%E 0 %. E 000 a~~~ 112 z w w z I- (o 3 a z I- , L 6- z 0 (0 .- z FI" 0 < ~1IL 00 w 4..Ill 2 u- 0 z 10 'i la 0 z a 0 0 0 a 0 2 0 .In- la SECOND INTERNATIONAL INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS. 1 TABLE 4 FREQUENCY OF SIDE-EFFECTS BY SYMPTOM GROUPS FOR THE THA AND TH REGIMENS a Patients with Treatment Treatment Treatment | Major departure Symptom Regi- side-effects not interrupted interrupted stopped from prescribed group men _ treatment No.| %__ No. % No. % No. % No. I %I- 1- 61 89 76 62 35 35 22 22 0 36 34 134 142 10.4 15.3 9 14 1.5 2.4 5 10 0.9 1.7 8 11 13.0 37 6.3 25 4.3 45 10.7 31 5.3 22 3.8 42 6.0 4 0.7 0 0.0 2 6.0 10 1.7 2 0.3 4 3.8 2 0.3 3 0.5 3 3.8 4 0.7 3 0.5 4 0.0 0.2 6.2 5.9 22.9 24.4 0 0 19 11 53 48 0.0 0.0 3.3 1.9 9.1 8.3 3 9 6 30 33 0.2 0.5 1.5 1.0 5.1 5.7 1 3 20 14 55 55 1.4 1.9 7.7 j7.2 0.3 0.7 0.5 0.7 0.2 0.5 3.4 2.4 ~i 9.4 9.5 a Based on 584 THA and 581 TH patients. b For details of regimens, see Table 1. Frequency ofside-effects The frequency of side-effects is set out in Table 4 according to the clinical action taken. Considering, first, the total side-effects, of 584 patients on the THA regimen, 37.2% had 1 or more side-effects compared with 38.4% of 581 patients on the TH regimen. The proportions were very similar whatever clinical action was taken; 9.4% and 9.5%, respectively, had experienced a major departure from the prescribed treatment. Considering, next, the side-effects by symptom group there was, on the whole, little difference between the two regimens. In particular, there were similar proportions of major departures from pre- scribed treatment as shown in Table 4 and in the following tabulation: THA patients (%) 1.4 7.7 0.3 0.5 0.2 3.4 TH patients (%) 1.9 7.2 0.3 0.7 0.5 2.4 Side-effect Gastric Cutaneous Vestibular Neurological Haematological Miscellaneous Of the patients with haematological side-effects, 1 on each regimen developed agranulocytosis. The frequency of some of the more important individual side-effects is given in Table 5. Vomiting occurred in 2.9% of patients on the THA and 5.9% on the TH regimen (P = 0.02), a major departure from treatment occurring in only 1 and 3 patients, respectively. Jaundice or hepatitis occurred in 4 THA TH THA TH THA TH THA TH 75 113 138 115 39 47 27 29 12.8 19.4 23.6 19.8 6.7 8.1 4.6 5.0 Gastric Cutaneous Vestibular Neurological Haematological Miscellaneous Total THA TH THA TH THA TH 4 64 51 217 223 0.2 0.7 11.0 8.8 37.2 38.4\ . 113 A. B. MILLER AND OTHERS TABLE 5 FREQUENCY OF VARIOUS SIDE-EFFECTS FOR THE THA AND TH REGIMENS a IT Patients with Treatment not Treatment Treatment Major departure Side-effect |Regi- side-effects interrupted Interrupted stopped from prescribed No. % No. % No. % No. % No. % THA 17 2.9 13 2.2 3 0.5 1 0.2 1 0.2 Vomiting TH 34 5.9 25 4.3 7 1.2 2 0.3 3 0.5 Jaundice or THA 4 0.7 1 0.2 1 0.2 2 0.3 3 0.5 hepatitis TH 4 0.7 0 0.0 0 0.0 4 0.7 4 0.7 Rash THA 113 19.3 53 9.1 36 6.2 24 4.1 44 7.5 TH 89 15.3 41 7.1 29 5.0 19 3.3 40 6.9 a Based on 584 THA and 581 TH patients. b For details of regimens, see Table 1. (0.7 %) patients on each regimen. There were more patients with a rash on the THA regimen-namely, 19.3% compared with 15.3% on the TH regimen (P= 0.08), a major departure from treatment occurring in 7.5% and 6.9 %, respectively. There was also no evidence that the severity of the rashes was reduced by the additives (the findings are not tabulated here). Summarizing, the over-all frequency of side-effects in the two regimens was very similar, although there were fewer gastric side-effects and rather more rashes in patients on the THA regimen. Frequency ofside-effects according to country The frequency of side-effects in the different countries is summarized in Table 6. In Algeria, Pakistan and Trinidad, more side-effects were reported in patients on the THA regimen. The differences were small, however, and even in India, where 37% of 270 patients on the THA regimen compared with 43% of 276 patients on the TH regimen had reports of side-effects, the difference was not statistically significant (P = 0.17), while the numbers of patients with a major departure from treatment in India were also small-namely, 7% and 9 %, respectively. A detailed analysis of the individual side-effects within countries showed that the differences between the two regimens were generally small (the findings for vomiting and the rashes are given in Appendix, Table 1). There was also no evidence that pre- treatment factors, especially weight, affected the differences between the regimens. Results ofroutine investigations There was no evidence that the additives influenced changes in haemoglobin levels or the occurrence of proteinuria or glycosuria over the 12-week period (the findings are not tabulated here). THE INFLUENCE OF ADDITIVES ON SIDE-EFFECTS TO THE STREPTOMYCIN PLUS THIOACETAZONE PLUS ISONIAZID REGIMEN AND ON THE STREPTOMYCIN PLUS ISONIAZID REGIMEN Condition on admission to treatment The condition on admission to treatment is set out in Table 7. The patients from Czechoslovakia were heavier than those in all other countries, their average weight being 65.4 kg. The distributions of pretreatment factors for the four regimens within each country were very similar (the findings are not tabulated here) and therefore the patients on the individual regimens have been amalgamated. The distributions for the four regimens were all very similar. Deaths During the 12-week period 16 (3 STHA, 4 STH, 5 SHA, 4 SH) patients died: 12 (1 STHA, 2 STH, 5 SHA, 4 SH) of tuberculosis, 2 (1 STHA, 1 STH) of 114 SECOND INTERNATIONAL INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS. 1 115 TABLE 6 FREQUENCY OF SIDE-EFFECTS ACCORDING TO COUNTRY FOR THE THA AND TH REGIMENS Patients with side-effects Country Regimen a paTtl°otal Treatment not Treatment Treatment Major departurepatients Toa I1nterrupted Interrupted stopped frmpecidtreatment No. %b No. %b No. %b No. %b No. %b THA 58 22 38 18 31 2 3 2 3 3 5 Algeria TH 58 17 29 13 22 3 5 1 2 1 2 THA 30 0 0 0 0 0 0 0 0 0 0 Ethiopia TH 29 1 3 1 3 0 0 0 0 0 0 THA 270 99 37 73 27 14 5 12 4 19 7 India TH 276 118 43 81 29 19 7 18 7 26 9 THA 47 26 55 8 17 12 26 6 13 8 1 7 M TH 48 27 56 5 10 14 29 8 17 12 25 THA 23 4 (17) 2 (9) 2 (9) 0 (0) 1 (4) Mongolia TH 23 4 (17) 1 (4) 2 (9) 1 (4) 2 (9) THA 69 15 22 12 17 2 3 1 1 2 3 Pakistan TH 65 10 15 9 14 1 2 0 0 1 2 THA 62 38 61 15 24 20 32 3 5 15 24 Singapore TH 64 39 61 27 42 9 14 3 5 11 17 THA 25 13 52 6 24 1 4 6 24 7 28 Trinidad TH 18 7 (39) 5 (28) 0 (0) 2 (11) 2 ( 1) THA 584 217 37.2 134 22.9 53 9.1 30 5.1 55 9.4 AH countries TH 581 223 38.4 142 24.4 48 8.3 5.7 55 9.5 a For details of regimens, see Table 1. b Values in parentheses denote percentages based on fewer than 25 observations. exfoliative dermatitis, 1 (STH) of an anaphylactoid died in the fifth week in spite of the administration reaction and 1 (STHA) of an unknown cause. of intravenous fluids and steroids. The STH patient Considering the deaths from tuberculosis in only developed fever followed by a generalized rash in the 4 (2 SHA, 2 SH) patients were side-effects reported sixth week and treatment with the tablets was stopped but they did not contribute to the cause of (streptomycin had been stopped 2 weeks before death. because of severe giddiness). The rash was confluent Considering the deaths from exfoliative dermatitis, and haemorrhagic and led to exfoliation accompanied the STHA patient developed fever followed by a by stomatitis and conjunctivitis. The patient dete- petechial rash in the third week. The rash rapidly riorated and died in the eighth week. became generalized and was accompanied by The STH patient who died of an anaphylactoid stomatitis. Treatment was stopped after 8 days but reaction developed severe generalized itching and exfoliation developed 4 days later and the patient flushing with marked hypotension and severe shock 116 A. B. MILLER AND OTHERS TAI CONDITION ON ADMISSION TO TREATMENT OF PATIEN Algeria clzechoi | Ethiopia India Malaysia | Mongolia No. % No. % No. % No. % No. % No. % Total patients 231 100 203 100 116 100 1121 100 202 100 92 |1O Sex Male 143 62 152 75- 83 72 854 76 164 81 46 50 Female 88 38 51 25 33 28 267 24 38 19 46 50 Age (years) 15-24 97 42 68 33 53 46 343 31 51 25 38 41 25-34 62 27 44 22 49 42 392 35 40 20 24 35-44 27 12 43 21 12 10 240 21 38 19 13 45-54 24 10 37 18 2 2 110 10 40 20 12 1 >55 21 9 11 5 0 0 36 3 33 16 5 8 Haemoglobin (g/100 ml) 6.0-7.9 1 0 0 0 0 0 51 4 9 4 0 0 8.0-9.9 15 6 0 0 2 2 261 23 37 18 12 13 10.0-11.9 82 35 4 2 11 9 549 49 76 38 54 59 >12.0 133 58 199 98 103 89 260 23 80 40 26 28 Weight <36.4 kg (80 lb) 9 4 0 0 3 3 242 22 7 3 1 1 36.4 kg-45.0 kg (80 lb-9 lb) 49 21 2 1 38 33 570 51 86 43 27 291 45.5 kg-54.1 kg (100 lb-119 lb) 90 39 26 13 51 44 287 26 81 40 38 41 >54.5 kg (120 lb) 83 36 175 86 24 21 22 2 28 14 26 28 Average weight (kg) 51.2 65.4 48.5 41.2 46.7 49.5 (lb) 112.6 143.9 106.7 90.7 102.7 108.9 a For details of the regimens see Table 1. 1 hour after taking the first study tablet and died Frequency ofside-effects 4 days later. Streptomycin had not been given. Table 8 shows the frequency of side-effects by It was then learnt that the patient had had a severe symptom group for the STHA and STH regimens. rash with pruritus after taking a single tablet of Of the 707 STHA patients, 50.5% had reports of unknown composition for tuberculosis 6 months side-effects compared with 50.1 % for the 689 STH before and had taken 1 month to recover. patients; amajor departure from prescribed treatment The STHA patient who died of an unknown cause occurred in 20.7% and 19.0%, respectively. Major collapsed and died in the ninth week approximately departures from prescribed treatment on account of 18 hours after complaining of colicky generalized specified side-effects are shown in Table 8 and in abdominal pain. the following tabulation: 117SECOND INTERNATIONAL INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS. 1 N THE STREPTOMYCIN-CONTAINING REGIMENSa | ~~~~~~~~~~Allcountries Morocco Pakistan Singapore jTrinidad A coutriS ____ _____ ____ ____ Trinidad ~~~~~STHA STH SHA SH No. | % No. % No. % No. |% No. % No. % % No. % 157 100 280 100 320 100 81 100 707 100 689 100 696 100 711 1On 95 61 195 70 253 79 52 64 512 72.4 500 72.6 509 73.1 516 72.6 62 39 85 30 67 21 29 36 195 27.6 189 27.4 187 26.9 195 27.4 75 48 88 31 71 22 13 16 215 30.4 239 34.7 225 32.3 218 30.7 39 25 100 36 70 22 16 20 213 30.1 201 29.2 211 30.3 211 29.7 33 21 60 21 74 23 18 22 147 20.8 140 20.3 125 18.0 146 20.5 9 6 26 9 67 21 15 19 87 12.3 76 11.0 92 13.2 87 12.2 1 1 6 2 38 12 19 23 45 6.4 33 4.8 43 6.2 49 6.9 0 0 8 3 4 1 1 1 19 2.7 23 3.3 13 1.9 19 2.7 10 6 50 18 34 11 10 12 115 16.3 92 13.4 116 16.7 108 15.2 38 24 118 42 179 56 29 36 274 38.8 286 41.5 275 39.5 295 41.5 109 69 104 37 113 35 41 51 299 42.3 288 41.8 292 42.0 289 40.6 1 1 21 8 18 6 0 0 78 11.0 69 10.0 84 12.1 71 10.0 40 25 109 39 131 41 19 23 278 39.3 276 40.1 261 37.5 256 36.0 69 44 110 39 132 41 22 27 223 31.5 208 30.2 232 33.3 243 34.2 47 30 40 14 39 12 40 49 128 18.1 136 19.7 119 17.1 141 19.8 49.9 109.7 46.3 101.9 46.3 101.8 53.1 116.8 46.6 102.6 46.7 102.7 46.4 102.0 47.1 103.5 STHA patients STH patients Side-effect treatment occurring in 1.4% and 4.5 %, respectively 3.3 6.4 Gastric (P < 0.001), both streptomycin and the oral medica- 10.6 9.1 Cutaneous ment being interrupted or stopped in the great 10.9 11.2 Vestibular majority of patients. Jaundice or hepatitis occurred 1.6 1.7 Neurological in 5 patients on the STHA regimen but in none 0.3 0.0 Haematological of the STH patients (P = 0.07). Rashes occurred in 3.5 2.8 Miscellaneous 19.8% of the STHA and 16.5% of the STH patients Considering the frequency of the more important (P = 0.13), resulting in a major departure from individual side-effects encountered in the STHA and prescribed treatment in 9.3 % and 7.8 % respectively STH regimens (Table 9), vomiting occurred in 6.2% (P = 0.4). of the STHA and 14.4% of the STH patients A detailed analysis of the individual side-effects (P< 0.00001), a major departure from prescribed within countries showed that the differences between _ A. B. MILLER AND OTHERS TABLE 8 FREQUENCY OF SIDE-EFFECTS BY SYMPTOM GROUPS FOR THE STHA AND STH REGIMENSa Patients with Treatment not Treatment Treatment Major departure Symptom Regi- side-effects interrupted interrupted stopped from prescribed group menb No.|No. No. % No. | % No | % No. % STHA 127 18.0 96 13.6 16 2.3 15 2.1 23 3.3 Gastric STH 164 23.8 105 15.2 41 6.0 18 2.6 44 6.4 STHA 175 24.8 84 11.9 58 8.2 33 4.7 75 10.6 Cutaneous STH 143 20.8 65 9.4 49 7.1 29 4.2 63 9.1 STHA 218 30.8 128 18.1 52 7.4 38 5.4 77 10.9 Vestibuiar STH 227 32.9 136 19.7 56 8.1 35 5.1 77 11.2 STHA 60 8.5 45 6.4 12 1.7 3 0.4 11 1.6 Neurological STH 48 7.0 33 4.8 7 1.0 8 1.2 12 1.7 STHA 3 0.4 1 0.1 1 0.1 1 0.1 2 0.3 Haematological STH 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 STHA 83 11.7 52 7.4 21 3.0 10 1.4 25 3.5 Miscellaneous STH 56 8.1 31 4.5 17 2.5 8 1.2 19 2.8 STHA 357 50.5 184 26.0 100 14.1 73 10.3 146 20.7 Total STH 345 50.1 183 26.6 100 14.5 62 9.0 131 19.0 a Based on 707 STHA and 689 STH patients. b For details of regimens, see Table 1. TABLE 9 FREQUENCY OF VARIOUS SIDE-EFFECTS FOR THE STHA AND STH REGIMENS a Patients with Treatment not Treatment Treatment Major departure Side-effect mRegi- side-effects interrupted interrupted stopped from prescribedSide-effe men b Itreatment|_ |_ No.1| % Nllo.1| % |No. % No. % No.[ % STHA 44 6.2 30 4.2 8 1.1 6 0.8 10 1.4 Vomiting STH 99 14.4 55 8.0 34 4.9 10 1.5 31 4.5 Jaundice or STHA 5 0.7 2 0.3 1 0.1 2 0.3 3 0.4 hepatitis STH 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 STHA 140 19.8 61 8.6 50 7.1 29 4.1 66 9.3 RashI STH 114 16.5 48 7.0 41 6.0 25 3.6 54 7.8 a Based on 707 STHA and 689 STH patients. b For details of regimens, see Table 1. 118 SECOND INTERNATIONAL INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS. 1 the two regimens were, in general, small (see Ap- pendix Table 2 for findings on vomiting and rashes). No evidence was found to show that any pre- treatment factor, particularly weight, had affected the differences between the regimens. Turning now to the patients in the SHA and SH regimens (Table 10), 31.8% of the 696 SHA and 30.4% of the 711 SH patients had side-effects, a major departure from prescribed treatment oocurring in 6.2% and 6.0%, respectively. The frequency was very similar in all symptom groups, as was the fre- quency of the more important individual side-effects (findings not tabulated here). A detailed analysis of the individual side-effects within countries showed that the differences between the two regimens were generally small (see Appendix Table 3 for findings on vomiting and rashes). There was no evidence to show that pre-treatment factors, in particular weight, affected the differences between regimens. Summang, the additives reduced vomiting in patients on the STHA regimen but had little effect on the frequency of the other side-effects. Over-all, there was no significant difference in the total incidence of side-effects or in the more serious side- effects. Results of routine investigations There was no evidence that the additives influenced changes in haemoglobin or the occurrence of proteinuria or glycosuria over the 12-week period (the findings are not tabulated here). DISCUSSION Although Mertens & Bunge (1950) reported that antihistamines were of value in treating gastric and cutaneous side-effects to thioacetazone, the first recommendation that an antihistamine should be used as a routine with thioacetazone appears to have TABLE 10 FREQUENCY OF SIDE-EFFECTS BY SYMPTOM GROUPS FOR THE SHA AND SH REGIMENSa Patients with Treatment not Treatment Treatment Majo prture Symptom Regi- side-effects Interrupted interrupted stopped treatment group men treatment___ No. % No. % No. % N o. % | No. % SHA 58 8.3 46 6.6 8 1.1 4 0.6 8 1.1 Gastric SH 66 9.3 57 8.0 7 1.0 2 0.3 5 0.7 SHA 87 12.5 68 9.8 15 2.2 4 0.6 16 2.3 Cutaneous SH 79 11.1 60 8.4 11 1.5 8 1.1 16 2.3 SHA 111 15.9 80 11.5 26 3.7 5 0.7 24 3.4 Vestibular SH 109 15.3 75 10.5 27 3.8 7 1.0 25 3.5 SHA 29 4.2 20 2.9 7 1.0 2 0.3 8 1.1 Neurological SH 35 4.9 26 3.7 7 1.0 2 0.3 7 1.0 SHA 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Haematological * SH 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 SHA 45 6.5 33 4.7 10 1.4 2 0.3 8 1.1 Miscellaneous SH 37 5.2 30 4.2 5 0.7 2 0.3 7 1.0 SHA 221 31.8 165 23.7 43 6.2 13 1.9 43 6.2 Total SH 216 30.4 157 22.1 41 5.8 18 2.5 43 6.0 a Based on 696 SHA and 711 SH patients. b For details of regimens, see Table 1. 119 A. B. MILLER AND OTHERS been made by Deshmukh & Master (1962) on the basis of a preliminary trial of thioacetazone plus isoniazid with buclizine hydrochloride in 25 patients. Other physicians in India subsequently reported their experience with formulations of thioacetazone plus isoniazid incorporating additives (Patel 1964; Chandrasekhar, Maribasappa & Rajasekhara, 1964; Menon, 1965) using buclizine as the antihistamine and vitamins of the B-complex plus calciferol. They found that the frequency of side-effects to thioacetazone when additives were used was low and of an acceptable level. Patel, Patel & Mehta (1965) reported a controlled, though not double-blind, trial of two regimens of isoniazid plus thioacetazone, one with buclizine and vitamins of the B-complex plus calciferol as additives. Changes in medication on account of toxicity were required in 3 of 67 patients who did not receive additives but in none of the 44 on additives. Subse- quently, preparations containing the additives in the dosages investigated in the present study have become a standard medication, extensively used in India and other parts of Asia. Thioacetazone side-effects with these preparations have been reported by some physicians (Bhupati, 1968; Sarma & Subramanyam, 1968; Purohit & Murthy, 1969) but not by others (Rao, 1968; Singh & Varma, 1968). The results of the present investigation show that over a 12-week period of treatment the additives, which are used extensively in India and in other parts of Asia, do not reduce the total frequency of symp- toms recorded as side-effects, or the frequency of side-effects requiring a major departure from the prescribed treatment, whether treatment was with thioacetazone plus isoniazid or with streptomycin plus thioacetazone plus isoniazid. Thus the total frequency of side-effects on the thioacetazone plus isoniazid regimen without the additives was 38%/ compared with 37% with the additives, a major departure from the prescribed treatment occurring in 9% of each series. Similarly, the additives did not reduce the total frequency of side-effects to streptomycin plus thioacetazone plus isoniazid and major departures from prescribed treatment oc- curred in 19% without the additives compared with 21 % with the additives. - The additives, however, reduced the frequency of vomiting. Thus for thioacetazone plus isoniazid, vomiting occurred in 6% patients without the additives and in 3% with them (P= 0.02). For streptomycin plus thioacetazone plus isoniazid, vomiting occurred in 14% without the additives and in 6% with them, a major departure from prescribed treatment occurring in 4% and 1%, respectively (P <0.001). This effect may be due to the anti- emetic action of buclizine (Pharmaceutical Society of Great Britain, 1967) or pyridoxine. Pyridoxine is of value in radiation sickness (Stoll, 1962) and in vomiting of pregnancy (General Practitioner Research Group, 1963). It does not, however, increase the anti-emetic action of an antihistamine in the treatment of vomiting of pregnancy (Diggory & Tomkinson, 1962) and "it is doubtful if this agent is significantly anti-emetic" (Brit. med. J., 1970). The apparently beneficial effect of the additives on this one side-effect must be viewed in relation to all the other, and in particular the more serious, side-effects which the additives certainly failed to reduce. For example, rashes occurred in 15% of patients on thioacetazone plus isoniazid without the additives but in 19% of those on the same regimen with the additives (P=0.08) and when streptomycin plus thioacetazone plus isoniazid was used, rashes occurred in 17% without the additives and in 20% with them (P= 0.13). It is relevant that it has been reported that antihistamines may cause aggravation of non-urticarial drug eruptions (Mackie & Mackie, 1966). In view of the potential severity of many cutaneous side-effects and the absence of benefit from additives now demonstrated, considerable caution is obviously required in advising the use of prophylactic antihistamine-containing additives in routine practice, particularly in areas where skin reactions from thioacetazone are likely to be common and not necessarily reported (Gothi, O'Rourke & Baily, 1966). It is not surprising that peripheral neuritis was not a problem in any series in this study since the dose of isoniazid (300 mg daily) was too low to be likely to cause peripheral neuritis (Devadatta et al., 1960) and therefore no useful purpose is served by adding pyridoxine when isoniazid is being given in con- ventional dosages (Tuberculosis Chemotherapy Centre, Madras, 1963). The similarity in the over-all frequency of side- effects when thioacetazone plus isoniazid or strepto- mycin plus thioacetazone plus isoniazid are used with and without the additives suggests that the additives produce few side-effects. This is further confirmed by the evidence available in the present study from the comparison of the two streptomycin plus isoniazid regimens, one with and the other without the additives. The total frequency of side- 120 SECOND INTERNATIONAL INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS. 1 effects among the patients receiving the additives was 31 % compared with 30% for those not re- ceiving additives; the proportion of patients with a major departure from prescribed treatment was 6% in each series. Increased cost and impaired keeping properties, especially in the tropics, are disadvantages of incor- porating additives in thioacetazone plus isoniazid tablets. Overages of 5 %/0-30% ofvitamins were neces- sary in the tablets used in the present study in order to allow for the possibility of loss during storage. Even so, the recommended shelf-life was only 12-18 months whereas standard preparations of thioacetazone plus isoniazid without additives remain fully potent for several years. Furthermore, the tab- lets of thioacetazone plus isoniazid with additives commercially available in Asia cost SUS7.6 for 1 year's treatment compared with SUS1.8 for 1 year's treatment with thioacetazone plus isoniazid without additives. In conclusion, this study has not demonstrated any over-all benefit following the use of an additive supplement of vitamins and an antihistamine as a prophylactic in preventing side-effects to thio- acetazone plus isoniazid regimens, with or without streptomycin. The use of the additive supplement as a prophylactic is therefore unjustified and cannot be recommended. ACKNOWLEDGEMENTS The following physicians and hospitals co-operated in the investigation: Physicians. Dr Abdul Aziz, Dr J. L. Bhatia, Dr P. S. Cheong, Dr M. Dan, Dr L. E. Dasent, Dr S. Devi, Dr H. B. Dingley, Dr S. Doraisingham, Dr D. Gombojav, Dr N. Halatchev, Dr R. Hanak, Dr Abdul Khaliq, Dr M. Klouche, Dr A. K. Koleh, Dr J. C. Kothari, Dr P. Kotaiah, Dr K. V. Krishnaswami, Dr R. Krut9, Dr C. Leonelli, Dr M. K. Mahmud, Dr M. Masuduzza- man, Dr J. Moisant, Dr A. Mounedji, Dr S. Muthus- wami, Dr N. Oussedik, Dr A. G. Patel, Dr J. Pavlica, Dr S. M. Quraishi, Dr L. Rahman, Dr Y. Rajasekhara, Dr A. P. Rao, Dr K. C. Rastogi, Dr Ren6e Ras, Dr R. K. Richardson, Dr S. P. Sadhu, Dr S. A. Shah, Dr L. Sitavanc, Dr J. S. Sodhy, Dr S. D. Store, Dr J. M. J. Supramaniam, Dr J. Susteric, Dr K. Virsik, Dr Moham- mad Iqbal Yad, Dr S. A. Yeoh. Hospitals. Algeria: H6pital Civil de Beni-Messous, Alger. Czechoslovakia: Regional Hospital of Tubercu- losis, Bratislava; Krajska Tuberkul6zna Lieceblia, Nitra- Zobor. Ethiopia: St Peter's T.B. Sanatorium, Addis Ababa. India: K. J. Mehta T.B. Hospital, Amargadh; T.B. Sanatorium, Amritsar; S.D.S. Sanatorium, Bangalore; S.P. Sanatorium, Baroda; Group of T.B. Hospitals, Bombay; Ramalingam Tuberculosis Sana- torium, Coimbatore District; M.R. Bangur Sanatorium, Digri; L.G.B. Chest Hospital, Gauhati; Hospital for Diseases of Chest and Tuberculosis, Hyderabad; The Tuberculosis Hospital, Mehrauli Road, New Delhi; Government Tuberculosis Sanatorium, Tambaram, Ma- dras. Malaysia: National Tuberculosis Centre, Kuala Lumpur. Mongolia: Tuberculosis Hospital for Adults, Ulan Bator. Morocco: Hopital Ibn Al Khatib, Fes; H8pital Sidi SaId, Meknes. Pakistan: Institute ofDiseases of the Chest & Hospital, Dacca; Ojha Sanatorium, Karachi; King Edward Medical College, Lahore; Miss Fatimah Jinnah T.B. Sanatorium, Quetta. Singapore: Tan Tock Seng Hospital. Trinidad: Caura Chest Hospital. We are grateful to Smith & Nephew Pharmaceuticals Ltd. (in particular to Mr S. R. Woods) who manufactured specially, and donated, all the oral medicament (thio- acetazone plus isoniazid with additives, thioacetazone plus isoniazid with placebo, the isoniazid with additives and isoniazid with placebo tablets) for this investigation and undertook the air freightage of the oral medicament and study documents to every co-operating centre. We are also grateful to the World Health Organiza- tion, and to the WHO South-East Asia Regional Office, for assistance in organizing this investigation. We are also grateful to the Governments of the 10 countries concerned for their permission to undertake the investigation in the co-operating hospitals, and, in particular, in Algeria to Dr L. Mokhtari, Chef du Bureau de la Tuberculose, Ministre de la Sant6, Alger; in Czecho- slovakia to Professor Dr H. Raskova, Pharmacological Institute of the Academy of Science, Prague, and to Dr K. Toman, Postgraduate Medical School, Prague; in Ethiopia to Ate Haile Guade, Director in the Ministry of Public Health; in India to Dr N. L. Bordia, Adviser in Tuberculosis to the Government of India, and to Col. B. L. Taneja, succeeded by Dr P. M. Wahi, Director of the Indian Council of Medical Research; in Malaysia to Tan Sri Dr Mohamed Din Bin Ahmad, Director- General of Medical Services; in Mongolia to Dr N. Chuluun, Chief T.B. Medical Officer; in Morocco to Dr H. Radenac, M6decin-Chef du Service Central de Lutte Antituberculose; in Pakistan to Dr rM. Hasan, Directorate of Tuberculosis Control, Karachi; in Singapore to Dr G. L. Ho, Director of Medical Services; in Trinidad to Dr Commissiong, Chief Medical Officer. 121 122 A. B. MILLER AND OTHERS RtSUMIE DEUXIEME ENQUETE COLLECTIVE INTERNATIONALE SUR LES EFFETS SECONDAIRES DE LA THIOACETAZONE: 1. INFLUENCE DE L'ADMINISTRATION CONCOMITANTE DE VITAMINES ET D'UN ANTIHISTAMINIQUE On a 6tudie l'action prophylactique sur les effets secondaires de la thioac6tazone de l'adjonction A la chimioth6rapie d'un traitement quotidien par vitamines (aneurine: 4 mg; riboflavine: 4 mg; pyridoxine: 6 mg; acide nicotinique: 40 mg; calcif6rol: 600 UI) et par antihistaminique (buclizine: 12 mg), traitment qui est couramment utilis6 en pratique clinique. Au total, 4210 patients, dans 10 pays, ont requ par 6chantillonnage aleatoire, pendant 12 semaines, l'une des associations th6rapeutiques suivantes: 150 mg de thioacetazone, 300 mg d'isoniazide, vitamines et buci- zine, en 1 comprim6 par jour (sch6ma THA); 150 mg de thioac6tazone, 300 mg d'isoniazide, placebo, en 1 comprim6 par jour (sch6ma TH); 1 g de streptomycine par voie intramusculaire, ainsi que 150 mg de thioac6- tazone, 300 mg d'isoniazide, vitamines et buclizine, en 1 comprim6 par jour (sch6ma STHA); 1 g de strepto- mycine par voie intramusculaire, ainsi que 150 mg de thioacetazone, 300 mg d'isoniazide, placebo, en 1 com- prim6 par jour (sch6ma STH); 1 g de streptomycine par voie intramusculaire, ainsi que 300 mg d'isoniazide, vitamines et buclizine, en 1 comprim6 par jour (sch6ma SHA); 1 g de stremtomycine par voie intramusculaire, ainsi que 300 mg d'isoniazide, placebo, en 1 comprim6 par jour (sch6ma SH). Les six schemas ont ete utilis6s en Alg6rie, en Ethiopie, en Inde, en Malaisie, en Mongolie, au Pakistan, i Singa- pour et a la Trinit6. En Tchecoslovaquie et au Maroc, les malades n'ont ete traites que par les associations comportant des injections de streptomycine. Les compri- mes, ind6pendamment de leur contenu, pr6sentaient la meme apparence et les investigations ont ete men6es selon la m6thode du double anonymat. Apres exclusion de l'enquete, pour diverses raisons, de 242 malades, on a fait port6 l'analyse sur 3968 patients, soit 584 malades THA, 581 TH, 707 STHA, 689 STH, 696 SHA et 711 SH. Des r6actions secondaires ont ete observ6es chez 37,2% des malades THA et chez 38,4% des malades TH; pour 9,4% et 9,5% d'entre eux, respectivement, le traitement a du 8tre interrompu, definitivement ou pour une dur6e de 7 jours ou plus. On a not6 des effets analogues chez 50,5% des malades STHA et chez 50,1% des malades STH (avec respectivement 20,7% et 19,0% d'interrup- tions de traitement), chez 31,8% des malades SHA et chez 30,4% des malades SH. Le seul r6sultat favorable de l'adjonction de vitamines et d'un antihistaminique au traitement chimioth6rapique a ete de r6duire la fr6quence des vomissements. II semble par contre que la pr6sence de l'antihistaminique dans les comprim6s a ete a l'origine d'un nombre plus 61ev6 d'6ruptions cutanees. Selon les auteurs, l'enquete montre que la prophy- laxie des effets secondaires de la thioac6tazone par les vitamines et la buclizine n'est en aucune facon justifi6e et ne peut etre recommand6e. REFERENCES Bhupati, D. (1968) Antiseptic, 65, 277 Brit. med. J., 1970, 1, 481 Chandrasekhar, B. M., Maribasappa, K. C. & Rajase- khara, Y. (1964) Indian Practit. 17, 799 Deshmukh, M. D. & Master, T. B. (1962) J. Indian med. Prof., 9, 4273 Devadatta, S., Gangadharam, P. R. J., Andrews, R. H., Fox, W., Ramakrishnan, C. V., Selkon, J. B. & Velu, S. (1960) Bull. Wld Hith Org., 23, 587 Diggory, P. L. C. & Tomkinson, J. S. (1962) Lancet, 2, 370 East African/British Medical Research Council Second Thiacetazone Investigation (1963) Tubercke (Edinb.), 44, 301 East African/British Medical Research Council Third Thiacetazone Investigation (1966) Tubercle (Edinb.), 47, 1 General Practitioner Research Group (1963) Practitioner, 190, 251 Gothi, G. D., O'Rourke, J. 0. & Baily, G. V. J. (1966) Indian J. Tuberc., 14, 41 Mackie, B. S. & Mackie, L. E. (1966) Med. J. Aust., 2^ 1034 Menon, N. K. (1965) Tubercle. (Edinb.), 46, 19 Mertens, A. & Bunge, R. (1950) Amer. Rev. Tuberc., 61, 20 Miller, A. B. Fox, W. & Tall, R. (1966) Tubercle (Edinb.), 47, 33 Patel, A. G. (1964) Curr. med. Pract., 8, 672 SECOND INTERNATIONAL INVESTIGATION INTO THIOACETAZONE SIDE-EFFECTS. 1 123 Patel, R. B., Patel, T. L. & Metha, H. C. (1965). Com- parative studies with isoniazid alone, isoniazid with thiacetazone and iosniazid with para-amino salicylic acid in ambulatory treatment ofpulmonary tuberculosis. In: Proceedings ofthe41stAlllndia Medical Conference, Baroda Pharmaceutical Society of Great Britain (1967) The Extra Pharmacopoeia, 25th ed., London, Pharmaceu- tical Press, p. 1186 Purohit, K. R. & Murthy, D. R. (1969) Antiseptic, 66, 27 Rao, M. V. (1968) Antiseptic, 65, 105 Sarma, 0. A. & Subramanyam, Y. (1968) Indian Prac- tit., 21, 481 Singh, H. K. & Varma, S. K. (1968) Mediscope, 9, 410 Stoll, B. A. (1962) Brit. med. J., 2, 507 Tuberculosis Chemotherapy Centre, Madras (1963) Bull. Wld Hlth Org., 29, 457 WHO Expert Committee on Tuberculosis (1964) Wld Hlth Org. tech. Rep. Ser., No. 290 APPENDIX TABLE I INCIDENCE OF VOMITING AND RASHES, ACCORDING TO COUNTRY, FOR THE THA AND TH REGIMENS Patients with vomiting Patients with rashes Total Major departure Major departureCountry Regimen pataln | Total from prescribed Total from prescribedpatients ~~~~~~treatment treatment l_____|___ - [ No. %a No. %a No. %Ga No.1 %_ THA 58 0 0 0 0 13 22 2 3 Algeria TH 58 2 3 0 0 4 7 0 0 THA 30 0 0 0 0 0 0 0 0 Ethiopia TH 29 0 0 0 0 0 0 0 0 THA 270 9 3 1 0 44 16 15 6 India TH 276 23 8 2 1 39 14 16 6 THA 47 1 2 0 0 13 28 6 13 Malaysia | TH 48 4 8 1 2 13 27 11 23 THA 23 0 (0) 0 (0) 4 (17) 1 (4) Mongolia TH 23 1 (4) 0 (0) 2 (9) 2 (9) THA 69 5 7 0 0 2 3 1 1 Pakistan TH 65 2 3 0 0 1 2 0 0 THA 62 1 2 0 0 27 44 14 23 Singapore TH 64 1 2 0 0 28 44 10 16 THA 25 1 4 0 0 10 40 5 20 Trinidad TH 18 1 (6) 0 (0) 2 (11) 1 (6) THA 584 17 2.9 1 0.2 113 19.3 44 7.5 All countries IAc tsTH | 581 | 34 5.9 3 j 0.5 J 89 15.3] 40 6.9 a Numbers in parentheses are percentages based on less than 25 observations. 124 A. B. MILLER AND OTIH S APPENDIX TABLE 2 INCIDENCE OF VOMITING AND RASHES, ACCORDING TO COUNTRY, FOR THE STHA AND STH REGIMENS Patients with vomiting Patients with rashes Total Major departure Major departureCountry Regimen p Total from prescribed Total from prescribedpatients ~~~treatment treatment No. %Ga No. %a No. % a No. i a Algeria STHA 60 1 2 1 2 13 22 3 5 STH 55 3 5 0 0 5 9 0 0 STHA 52 1 2 0 0 4 8 3 6 Czechoslovakia STH 49 1 2 1 2 4 8 4 8 STHA 28 1 4 0 0 0 0 0 0 Ethiopia STH 29 0 0 0 0 0 0 0 0 STHA 286 24 8 2 1 50 17 24 8 India STH 267 44 16 14 5 39 15 16 6 STHA 51 7 14 2 4 11 22 7 14 Malaysia STH 50 14 28 4 8 12 24 7 14 STHA 23 0 (0) 0 (0) 5 (22) 4 (17) Mongolia STH 24 0 (0) 0 (0) 1 (4) 0 (0) STHA 37 0 0 0 0 1 3 1 3 Morocco STH 42 0 0 0 0 1 2 1 2 STHA 71 2 3 0 0 7 10 0 0 Pakistan STH 68 7 10 0 0 5 7 3 4 STHA 79 6 8 4 5 38 48 19 24 STH 83 28 34 12 14 40 48 20 24 STHA 20 2 (10) 1 (5) 11 (55) 5 (25)Trinidad STH 22 2 (9) 0 (0) 7 (32) 3 (14) STHA 707 44 6.2 10 1.4 140 19.8 66 9.3 All countries STH 689 99 14.4 31 4.5 114 16.5 54 7.8 a Numbers In parentheses are percentages based on less than 25 observations. SECOND INTERNATIONAL INVETIGATION INTOTOIOACETAZONE SIDE-EFFEC 1 APPENDIX TABLE 3 INCIDENCE OF VOMITING AND RASHES, ACCORDING TO COUNTRY, FOR THE SHA AND SH REGIMENS Patients with vomiting Patients with rashes Total Major departure Major departureCountry Regimen patients Total from prescribed Total from prescribed treatment treatment No.1% . No. %a No. % - No. %a SHA 58 2 3 0 0 5 9 2 3 Algeria SH 58 3 5 1 2 4 7 0 0 SHA 50 0 0 0 0 4 8 1 2 Czechoslovakia SH 52 0 0 0 0 1 2 1 2 SHA 28 0 0 0 0 0 0 0 0 Ethiopia SH 31 0 0 0 0 0 0 0 0 SHA 279 5 2 1 0 24 9 2 1 India SH 289 8 3 2 1 22 8 2 1 SHA 53 4 8 1 2 6 11 4 8 Malaysia SH 48 4 8 1 2 3 6 3 6 SHA 23 0 (0) 0 (0) 0 (0) 0 (0) SH 22 0 (0) 0 (0) 1 (5) 1 (5) SHA 40 0 0 0 0 1 2 0 0Morocco SH 38 0 0 0 0 2 5 1 3 SHA 66 1 2 0 0 2 3 0 0 Pakistan SH 75 1 1 0 0 2 3 0 0 SHA 81 4 5 2 2 15 19 1 1 Singapore SH 77 3 4 0 0 16 21 3 4 TrlinIdad SHA 18 0 (0) 0 (0) 3 (17) 0 (0) SH 21 0 (0) 0 (0) 3 (14) 1 (5) SHA 6s6 16 2.3 4 0.6 60 8.6 10 IA All countrIes SH 711 19 2.7 4 0.6 54 7.6 12 1.7 a Numbers In parentheses are percentages based on less than 25 observations. 9 125