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Serum uric acid concentrations and arthralgia among patients treated with pyrazinamide-containing regimens in Hong Kong and Singapore
Tubercle 62 (1981)
175-l
0
Ltd.
Longman
Group
0041-3879181
79
JO03201 75 $02.00
SERUM URIC ACID CONCENTRATIONS AND ARTHRALGIA AMONG PATIENTS TREATED WITH PYRAZINAMIDE-CONTAINING REGIMENS IN HONG KONG AND SINGAPORE P. J. Jenner* and G. A. Ellard* MRC Unit for Laboratory Studies of Tuberculosis, Royal Postgraduate Medical School, Du Cane Road, London W12 OHS, England
W. G. L. Allan Wanchai Chest Clinic, Kennedy Road, Hong Kong
Dhanwant Tan Tack Seng Hospital,
Singh
Moulmein
Road, Singapore
1130
D. J. Girling and A. J. Nunn MRC
Tuberculosis and Chest Diseases Unit, Brompton Hospital, Fulham Road, London SW3 6HP, England
Summary The serum uric acid concentrations of patients being treated in Hong Kong and Singapore with a daily regimen consisting of streptomycin, isoniazid, rifampicin and pyrazinamide or a control regimen of daily streptomycin, p-amino-salicylic acid (PAS) and isoniazid were determined by the phosphotungstate method. Arthralgia and elevated serum uric acid levels were encountered only during the period that patients were being treated with pyrazinamide. Although daily treatment with pyrazinamide increased serum uric acid concentrations approximately 2.5-fold, the concentrations of the 6 patients who developed arthralgia were closely similar to those of matched controls without arthralgia. This fails to confirm a previous suggestion that patients with arthralgia might have higher values. Rifampicin appeared not to influence the hyperuricaemic effect of pyrazinamide. R&urn6 On a determine par la methode au phosphotungstate les concentrations seriques d’acide urique de malades trait& a Hong Kong et a Singapour par un regime quotidien comprenant streptomycine, isoniazide, rifampicine et pyrazinamide ou par un regime temoin quotidien de streptomycine, p-amino-salicylique (PAS) et isoniazide. On a rencontre des arthralgies et des taux seriques augment& d’acide urique seulement au tours de la periode pendant laquelle les malades etaient trait& par le pyrazinamide. Bien que le traitement journalier par le pyrazinamide augmente les concentrations seriques d’acide urique environ 2,5 fois, les concentrations chez les six malades chez lesquels des arthralgies sont apparues Btaient tres proches de celles de temoins apaires sans arthralgie. II n’a done pas ete possible de confirmer une hypothese anterieure selon laquelle les malades presentant des arthralgies pourraient avoir des taux plus Bleves. La rifampicine ne semble pas avoir infuence I’effet hyper-uricemique du pyrazinamide. *Currentaddress-National
Institutefor
Medical
Research,The
Ridgeway,
Mill Hill, London
NW7 IAA
176
Jenner and others Resumen Se midio la concentration serica de acid0 uric0 por el metodo del fosfotungstato, en enfermos de Hong-Kong y Singapur tratados con un esquema cotidiano que contenia estreptomicina, isoniacida, rifampicina y pirazinamida con un esquema testigo cotidiano que contenia estreptomicina, acido p. amino salicilico (PAS) e isoniacida. Se observaron artralgias y niveles sericos de acid0 lirico aumentados, solo en el period0 durante el cual 10s enfermos fueron tratados con pirazinamida. A pesar de que el tratamiento diario con pirazinamida aumenta las concentraciones sericas de acid0 tirico alredador de 2,5 veces, en 10s 6 enfermos que presentaron artralgias, estas concentraciones eran similares a 10s de 10s testigos apareados sin artralgias. Asi, no fue posible confirmar una hipotesas anterior segljn la cual 10s enfermos con artralgias podrian tener niveles sericos m&s elevados de Bcido Qrico. La rifampicina no parece habertenido una infleuncia sobre el efecto hiperuricemico de la pirazinamida. Introduction
Recent controlled clinical trials have demonstrated the important role of pyrazinamide in short-course chemotherapy for pulmonary tuberculosis [I, 21. Because of this, pyrazinamide is likely to be increasingly used in first-line treatment. A not infrequent adverse reaction to pyrazinamide-containing regimens is arthralgia, which probably results from inhibition of the renal secretion of uric acid by pyrazinoic acid, the drug’s major metabolite in man [3]. Furthermore, in a recent study [4] in which patients were treated with daily, thrice-weekly and twice-weekly pyrazinamide-containing regimens, a correlation was demonstrated between the frequency of arthralgia, the degree of serum hyperuricaemia and the proportion of time during which the renal secretion of uric acid was inhibited. Also there was a suggestion (P=O.O7) that patients who developed arthralgia on the daily pyrazinamide-containing regimen had higher serum uric acid concentrations than did matched controls without arthralgia. This paper presents the results of further studies on the relationship between pyrazinamide treatment, serum uric acid concentrations and the frequency of arthralgia, undertaken in conjunction with controlled clinical trials in Hong Kong [5], and Singapore [6]. Methods Serum samples were obtained pretreatment and at 1, 2, and 3 months from 184 consecutive Chinese patients allocated to daily treatment for 2 or 3 months with streptomycin, isoniazid, rifampicin and pyrazinamide (2SHRZ and 3SHRZ regimens) or with a standard 12-month control regimen of streptomycin, PAS and isoniazid daily for 3 months, followed by streptomycin and isoniazid twice-weekly for the remaining 9 months (SPH/S,H, regimen). These patients were participating in a study carried out in Hong Kong to investigate the duration of short-course chemotherapy appropriate for the treatment of smear-negative pulmonary tuberculosis [S]. Serum samples were also obtained pretreatment and at 1 and 2 months from 138 consecutive smear-positive Chinese, Malay or Indian patients who had been randomly allocated to 2 months of daily treatment with streptomycin, isoniazid, rifampicin and pyrazinamide followed by daily treatment for a further 2 or 4 months with either isoniazid and rifampicin (2SH RZ/H R regimen) or isoniazid, rifampicin and pyrazinamide (2SH RZ/HRZ regimen) in Singapore [6]. In both studies, the pyrazinamide dosage was 1.5 g for patients weighing less than 50 kg and 2.0 g for heavier patients as a single daily dose. Serum samples were deep-frozen prior to being flown to London in solid carbon dioxide and were then stored over liquid nitrogen until all the samples had been collected. During
Uric acid concentrations
with pyrazinamide
177
this period, only 6 patients (all from Singapore) from whom samples were collected developed arthralgia. Uric acid concentrations were then determined using Folin’s phosphotungstate method [7] on samples from 26 of the 61 3SHRZ and 13 of the 58 SPH/S,H, Hong Kong patients (randomly selected), from the three 2SHRZ/HRZ and three 2SHRZ/HR Singapore patients who had arthralgia and from a further 18 Singapore patients who were matched for sex, race, age and regimen of chemotherapy with those who developed arthralgia. To prevent bias all serum samples were randomised and coded priorto analysis. Results The serum uric acid concentrations are summarised in Table I. The pretreatment mean concentrations in the serum samples from the Hong Kong and from the Singapore patients were similar. Treatment with the SPH/S*H 2 regimen in Hong Kong did not affect the serum uric acid concentrations, the means pretreatment and at months 1, 2 and 3 being similar. In contrast, daily treatment with pyrazinamide given together with streptomycin, isoniazid and rifampicin increased the mean serum uric acid concentration 2-fold to 3-fold, maximal mean levels being achieved within the first month and being similar in Hong Kong and Singapore, namely 0.71 and 0.75 mmol/l respectively. Analysis of variance of the serum uric acid concentrations pretreatment and at 1, 2 and 3 months in the SPH/S 2H 2 patients in Hong Kong showed that although these were uninfluenced by treatment with streptomycin, PAS and isoniazid, there were consistent between-patient differences (P~O.001). A similar analysis of the values obtained at I,2 and 3 months in the 3SHRZ patients showed significant differences (P~O.001) between the 26 patients during daily pyrazinamide treatment. Furthermore, significant correlations were demonstrated between the mean serum uric acid concentrations during daily pyrazinamide treatment and the pretreatment values for both the Hong Kong and Singapore patients (correlation coefficients 0.75 and 0.84 respectively ,P
Table I.
Effect of daily pyrazinamide
Centre
Hong
Regimen
Patients assessed
treatment on serum uric acid concentrations Mean serum uric acid concentration and standard deviation at month
(mmolfl)
0
1
2
3
0.71 + 0.22
0.70+
0.22
0.07
0.30&
0.08
0.28+
0.10
3SHRZ
26
0.31 + 0.10
0.71 + 0.23
SPH/SZHZ
13
0.31
f
0.08
0.272
PSHRZ
18
0.26
f
0.08
0.71
f
0.22
0.82
f
0.26
-
6
0.27
f
0.10
0.77
+ 0.18
0.66
f
0.20
-
Kong
Singapore* 2SH!?Z** *The 2SHRZ/HRZ and 2SHRZ/HR during the first 2 months. **Patients
with
arthralgia
regimens
are
combined
because
uric
acid
concentrations
were
measured
only
178
Jenner and others Discussion
In both the Hong Kong and Singapore studies arthralgia was encountered only while patients were receiving pyrazinamide. Its incidence approximated to 1 % per month of chemotherapy and appeared to be as common when pyrazinamide was combined with isoniazid and rifampicin as when it was given with isoniazid, rifampicin and streptomycin. In neither study was the arthralgia of any patient severe enough to warrant terminating the pyrazinamide treatment [5, 61. The pretreatment serum uric acid concentrations of both the Hong Kong and Singapore patients were similar to those in the previous Hong Kong study (4). The concentrations were uninfluenced by treatment with streptomycin, isoniazid and PAS but were increased approximately 2.5-fold by daily treatment with streptomycin, isoniazid, rifampicin and pyrazinamide to levels that were virtually identical to those encountered in patients treated with daily streptomycin, isoniazid and pyrazinamide but without rifampicin [4]. It is therefore highly likely that the simultaneous administration of rifampicin does not influence the hyperuricaemic effect of pyrazinamide. This is in accord with evidence that rifampicin affects neither the absorption of pyrazinamide nor its conversion to pyrazinoic acid (Ellard, G. A., unpublished results), and also with evidence from the present study and from the previous study (4) that the incidence of arthralgia during treatment with regimens containing pyrazinamide, which approximates to 1 % per month of chemotherapy, is uninfluenced by whether or not rifampicin is also given. Finally, the observation that serum uric acid concentrations of the Singapore patients who developed arthralgia were closely similar to those of the matched controls without arthralgia, fails to confirm the previous suggestion [4] that patients who develop arthralgia might have higher serum uric acid concentrations than those who do not. Acknowledgements The medical and laboratory staffs, the medical social workers, health visitors, and health auxilliaries, and the nursing, radiographic, technical, secretarial, and administrative staffs of the Wanchai, Sai Ying Pun, Shaukeiwan, Yaumati, Kowloon, East Kowloon, Shek Kip Mei and South Kwai Chung Government Chest Clinics, the Government Pathological Institute, Ruttonjee Sanatorium, and Grantham, Haven of Hope, and Kowloon hospitals in Hong Kong and of the Tan Tack Seng Hospital and the Primary Health Care Services in Singapore, cooperated in the study. The coordinating secretaries were Mr Y. L. Chan in Hong Kong and Nurses Foo Gwek Eng and RosalindTan in Singapore. We thank the Director of the Medical and Health Services in Hong Kong, Dr K. L. Thong, and also the former Director, Dr Ho Guan Lim, and Permanent Secretary and Director, Dr Andrew Chew Guan Khuan, Medical Services Singapore, for their encouragement and support; Singapore Airlines for a concessional rate for air freight, and the Ministry of Health, Singapore, for a research grant. Requests for reprints should be sent to Mr Jenner. References 1 Fox, W. (1979). 2 Mitchison,
The chemotherapy
D.A. (1979).
of pulmonary tuberculosis:
Basic mechanisms of chemotherapy.
a review. Chest, 76s. Chest, 76s.
785 S.
771 S.
3 Ellard, G. A., Et Haslam, Ft. M. (1976). Observations on the reduction of the renal elimination of urate in man caused by the administration of pyrazinamide. Tubercle, 57,97. 4 Hong
Kong Tuberculosis Treatment Services/British Medical Research Council. (1976). Adverse reactions to short-course regimens containing streptomycin, isoniazid, pyrazinamide and rifampicin in Hong Kong. Tubercle, 57,81.
Uric acid concentrations 6 Hong Kong Chest Service,Tuberculosis Research Centre, Madras, India,and Sputum-smear-negative pulmonary tuberculosis: Controlled trial
with pyrazinamide
179
British Medical Research Council. (1979). of 3-month and 2-month regimens of
chemotherapy. Lancer, 1, 1361. 6 Singapore Tuberculosis Service/British Medical Research Council. (1979). Clinical trial of six-month and four-month rsgimens of chemotherapy in the treatment of pulmonary tuberculosisAmerican Review ofRespiratoryDisease, 119, 579. 7 Henry, Ft. J., Sobel, C., Et Kim, J. (1957). A modified carbonatephosphotungstate method for the determination of uric acid and comparison with the spectra-photometric uricase method. American Journalof ClinicalPathology, 28. 645.
175-l
0
Ltd.
Longman
Group
0041-3879181
79
JO03201 75 $02.00
SERUM URIC ACID CONCENTRATIONS AND ARTHRALGIA AMONG PATIENTS TREATED WITH PYRAZINAMIDE-CONTAINING REGIMENS IN HONG KONG AND SINGAPORE P. J. Jenner* and G. A. Ellard* MRC Unit for Laboratory Studies of Tuberculosis, Royal Postgraduate Medical School, Du Cane Road, London W12 OHS, England
W. G. L. Allan Wanchai Chest Clinic, Kennedy Road, Hong Kong
Dhanwant Tan Tack Seng Hospital,
Singh
Moulmein
Road, Singapore
1130
D. J. Girling and A. J. Nunn MRC
Tuberculosis and Chest Diseases Unit, Brompton Hospital, Fulham Road, London SW3 6HP, England
Summary The serum uric acid concentrations of patients being treated in Hong Kong and Singapore with a daily regimen consisting of streptomycin, isoniazid, rifampicin and pyrazinamide or a control regimen of daily streptomycin, p-amino-salicylic acid (PAS) and isoniazid were determined by the phosphotungstate method. Arthralgia and elevated serum uric acid levels were encountered only during the period that patients were being treated with pyrazinamide. Although daily treatment with pyrazinamide increased serum uric acid concentrations approximately 2.5-fold, the concentrations of the 6 patients who developed arthralgia were closely similar to those of matched controls without arthralgia. This fails to confirm a previous suggestion that patients with arthralgia might have higher values. Rifampicin appeared not to influence the hyperuricaemic effect of pyrazinamide. R&urn6 On a determine par la methode au phosphotungstate les concentrations seriques d’acide urique de malades trait& a Hong Kong et a Singapour par un regime quotidien comprenant streptomycine, isoniazide, rifampicine et pyrazinamide ou par un regime temoin quotidien de streptomycine, p-amino-salicylique (PAS) et isoniazide. On a rencontre des arthralgies et des taux seriques augment& d’acide urique seulement au tours de la periode pendant laquelle les malades etaient trait& par le pyrazinamide. Bien que le traitement journalier par le pyrazinamide augmente les concentrations seriques d’acide urique environ 2,5 fois, les concentrations chez les six malades chez lesquels des arthralgies sont apparues Btaient tres proches de celles de temoins apaires sans arthralgie. II n’a done pas ete possible de confirmer une hypothese anterieure selon laquelle les malades presentant des arthralgies pourraient avoir des taux plus Bleves. La rifampicine ne semble pas avoir infuence I’effet hyper-uricemique du pyrazinamide. *Currentaddress-National
Institutefor
Medical
Research,The
Ridgeway,
Mill Hill, London
NW7 IAA
176
Jenner and others Resumen Se midio la concentration serica de acid0 uric0 por el metodo del fosfotungstato, en enfermos de Hong-Kong y Singapur tratados con un esquema cotidiano que contenia estreptomicina, isoniacida, rifampicina y pirazinamida con un esquema testigo cotidiano que contenia estreptomicina, acido p. amino salicilico (PAS) e isoniacida. Se observaron artralgias y niveles sericos de acid0 lirico aumentados, solo en el period0 durante el cual 10s enfermos fueron tratados con pirazinamida. A pesar de que el tratamiento diario con pirazinamida aumenta las concentraciones sericas de acid0 tirico alredador de 2,5 veces, en 10s 6 enfermos que presentaron artralgias, estas concentraciones eran similares a 10s de 10s testigos apareados sin artralgias. Asi, no fue posible confirmar una hipotesas anterior segljn la cual 10s enfermos con artralgias podrian tener niveles sericos m&s elevados de Bcido Qrico. La rifampicina no parece habertenido una infleuncia sobre el efecto hiperuricemico de la pirazinamida. Introduction
Recent controlled clinical trials have demonstrated the important role of pyrazinamide in short-course chemotherapy for pulmonary tuberculosis [I, 21. Because of this, pyrazinamide is likely to be increasingly used in first-line treatment. A not infrequent adverse reaction to pyrazinamide-containing regimens is arthralgia, which probably results from inhibition of the renal secretion of uric acid by pyrazinoic acid, the drug’s major metabolite in man [3]. Furthermore, in a recent study [4] in which patients were treated with daily, thrice-weekly and twice-weekly pyrazinamide-containing regimens, a correlation was demonstrated between the frequency of arthralgia, the degree of serum hyperuricaemia and the proportion of time during which the renal secretion of uric acid was inhibited. Also there was a suggestion (P=O.O7) that patients who developed arthralgia on the daily pyrazinamide-containing regimen had higher serum uric acid concentrations than did matched controls without arthralgia. This paper presents the results of further studies on the relationship between pyrazinamide treatment, serum uric acid concentrations and the frequency of arthralgia, undertaken in conjunction with controlled clinical trials in Hong Kong [5], and Singapore [6]. Methods Serum samples were obtained pretreatment and at 1, 2, and 3 months from 184 consecutive Chinese patients allocated to daily treatment for 2 or 3 months with streptomycin, isoniazid, rifampicin and pyrazinamide (2SHRZ and 3SHRZ regimens) or with a standard 12-month control regimen of streptomycin, PAS and isoniazid daily for 3 months, followed by streptomycin and isoniazid twice-weekly for the remaining 9 months (SPH/S,H, regimen). These patients were participating in a study carried out in Hong Kong to investigate the duration of short-course chemotherapy appropriate for the treatment of smear-negative pulmonary tuberculosis [S]. Serum samples were also obtained pretreatment and at 1 and 2 months from 138 consecutive smear-positive Chinese, Malay or Indian patients who had been randomly allocated to 2 months of daily treatment with streptomycin, isoniazid, rifampicin and pyrazinamide followed by daily treatment for a further 2 or 4 months with either isoniazid and rifampicin (2SH RZ/H R regimen) or isoniazid, rifampicin and pyrazinamide (2SH RZ/HRZ regimen) in Singapore [6]. In both studies, the pyrazinamide dosage was 1.5 g for patients weighing less than 50 kg and 2.0 g for heavier patients as a single daily dose. Serum samples were deep-frozen prior to being flown to London in solid carbon dioxide and were then stored over liquid nitrogen until all the samples had been collected. During
Uric acid concentrations
with pyrazinamide
177
this period, only 6 patients (all from Singapore) from whom samples were collected developed arthralgia. Uric acid concentrations were then determined using Folin’s phosphotungstate method [7] on samples from 26 of the 61 3SHRZ and 13 of the 58 SPH/S,H, Hong Kong patients (randomly selected), from the three 2SHRZ/HRZ and three 2SHRZ/HR Singapore patients who had arthralgia and from a further 18 Singapore patients who were matched for sex, race, age and regimen of chemotherapy with those who developed arthralgia. To prevent bias all serum samples were randomised and coded priorto analysis. Results The serum uric acid concentrations are summarised in Table I. The pretreatment mean concentrations in the serum samples from the Hong Kong and from the Singapore patients were similar. Treatment with the SPH/S*H 2 regimen in Hong Kong did not affect the serum uric acid concentrations, the means pretreatment and at months 1, 2 and 3 being similar. In contrast, daily treatment with pyrazinamide given together with streptomycin, isoniazid and rifampicin increased the mean serum uric acid concentration 2-fold to 3-fold, maximal mean levels being achieved within the first month and being similar in Hong Kong and Singapore, namely 0.71 and 0.75 mmol/l respectively. Analysis of variance of the serum uric acid concentrations pretreatment and at 1, 2 and 3 months in the SPH/S 2H 2 patients in Hong Kong showed that although these were uninfluenced by treatment with streptomycin, PAS and isoniazid, there were consistent between-patient differences (P~O.001). A similar analysis of the values obtained at I,2 and 3 months in the 3SHRZ patients showed significant differences (P~O.001) between the 26 patients during daily pyrazinamide treatment. Furthermore, significant correlations were demonstrated between the mean serum uric acid concentrations during daily pyrazinamide treatment and the pretreatment values for both the Hong Kong and Singapore patients (correlation coefficients 0.75 and 0.84 respectively ,P
Table I.
Effect of daily pyrazinamide
Centre
Hong
Regimen
Patients assessed
treatment on serum uric acid concentrations Mean serum uric acid concentration and standard deviation at month
(mmolfl)
0
1
2
3
0.71 + 0.22
0.70+
0.22
0.07
0.30&
0.08
0.28+
0.10
3SHRZ
26
0.31 + 0.10
0.71 + 0.23
SPH/SZHZ
13
0.31
f
0.08
0.272
PSHRZ
18
0.26
f
0.08
0.71
f
0.22
0.82
f
0.26
-
6
0.27
f
0.10
0.77
+ 0.18
0.66
f
0.20
-
Kong
Singapore* 2SH!?Z** *The 2SHRZ/HRZ and 2SHRZ/HR during the first 2 months. **Patients
with
arthralgia
regimens
are
combined
because
uric
acid
concentrations
were
measured
only
178
Jenner and others Discussion
In both the Hong Kong and Singapore studies arthralgia was encountered only while patients were receiving pyrazinamide. Its incidence approximated to 1 % per month of chemotherapy and appeared to be as common when pyrazinamide was combined with isoniazid and rifampicin as when it was given with isoniazid, rifampicin and streptomycin. In neither study was the arthralgia of any patient severe enough to warrant terminating the pyrazinamide treatment [5, 61. The pretreatment serum uric acid concentrations of both the Hong Kong and Singapore patients were similar to those in the previous Hong Kong study (4). The concentrations were uninfluenced by treatment with streptomycin, isoniazid and PAS but were increased approximately 2.5-fold by daily treatment with streptomycin, isoniazid, rifampicin and pyrazinamide to levels that were virtually identical to those encountered in patients treated with daily streptomycin, isoniazid and pyrazinamide but without rifampicin [4]. It is therefore highly likely that the simultaneous administration of rifampicin does not influence the hyperuricaemic effect of pyrazinamide. This is in accord with evidence that rifampicin affects neither the absorption of pyrazinamide nor its conversion to pyrazinoic acid (Ellard, G. A., unpublished results), and also with evidence from the present study and from the previous study (4) that the incidence of arthralgia during treatment with regimens containing pyrazinamide, which approximates to 1 % per month of chemotherapy, is uninfluenced by whether or not rifampicin is also given. Finally, the observation that serum uric acid concentrations of the Singapore patients who developed arthralgia were closely similar to those of the matched controls without arthralgia, fails to confirm the previous suggestion [4] that patients who develop arthralgia might have higher serum uric acid concentrations than those who do not. Acknowledgements The medical and laboratory staffs, the medical social workers, health visitors, and health auxilliaries, and the nursing, radiographic, technical, secretarial, and administrative staffs of the Wanchai, Sai Ying Pun, Shaukeiwan, Yaumati, Kowloon, East Kowloon, Shek Kip Mei and South Kwai Chung Government Chest Clinics, the Government Pathological Institute, Ruttonjee Sanatorium, and Grantham, Haven of Hope, and Kowloon hospitals in Hong Kong and of the Tan Tack Seng Hospital and the Primary Health Care Services in Singapore, cooperated in the study. The coordinating secretaries were Mr Y. L. Chan in Hong Kong and Nurses Foo Gwek Eng and RosalindTan in Singapore. We thank the Director of the Medical and Health Services in Hong Kong, Dr K. L. Thong, and also the former Director, Dr Ho Guan Lim, and Permanent Secretary and Director, Dr Andrew Chew Guan Khuan, Medical Services Singapore, for their encouragement and support; Singapore Airlines for a concessional rate for air freight, and the Ministry of Health, Singapore, for a research grant. Requests for reprints should be sent to Mr Jenner. References 1 Fox, W. (1979). 2 Mitchison,
The chemotherapy
D.A. (1979).
of pulmonary tuberculosis:
Basic mechanisms of chemotherapy.
a review. Chest, 76s. Chest, 76s.
785 S.
771 S.
3 Ellard, G. A., Et Haslam, Ft. M. (1976). Observations on the reduction of the renal elimination of urate in man caused by the administration of pyrazinamide. Tubercle, 57,97. 4 Hong
Kong Tuberculosis Treatment Services/British Medical Research Council. (1976). Adverse reactions to short-course regimens containing streptomycin, isoniazid, pyrazinamide and rifampicin in Hong Kong. Tubercle, 57,81.
Uric acid concentrations 6 Hong Kong Chest Service,Tuberculosis Research Centre, Madras, India,and Sputum-smear-negative pulmonary tuberculosis: Controlled trial
with pyrazinamide
179
British Medical Research Council. (1979). of 3-month and 2-month regimens of
chemotherapy. Lancer, 1, 1361. 6 Singapore Tuberculosis Service/British Medical Research Council. (1979). Clinical trial of six-month and four-month rsgimens of chemotherapy in the treatment of pulmonary tuberculosisAmerican Review ofRespiratoryDisease, 119, 579. 7 Henry, Ft. J., Sobel, C., Et Kim, J. (1957). A modified carbonatephosphotungstate method for the determination of uric acid and comparison with the spectra-photometric uricase method. American Journalof ClinicalPathology, 28. 645.