792
THE LANCET, OCTOBER
PROBENECID AND RIFAMPICIN SERUM LEVELS R. J. FALLON G. W. ALLAN W.
A. W.
LEES
J. SMITH F. TYRRELL
Department of Laboratory Medicine and Chest Department, Ruchill Hospital, Glasgow G20 9NB
Summary
Serum-levels of rifampicin were investigated in patients receiving rifampicin alone or with other antituberculosis drugs. 2 g of probenecid given 30 min before 300 mg of rifampicin did not result in raising serum levels to more than half those achieved with the standard 600 mg dose of rifampicin. Hence probenecid should not be used to reduce rifampicin dosage in antituberculosis therapy.
Introduction is not only the most effective companion for isoniazid in antituberculosis therapy, but also it has few troublesome side-effects and has the advantage of oral administration. It is, however, very expensive. To cut costs it has been given twice weekly instead of daily but this regimen, though effective, produces an unacceptably high incidence of allergic reactions. Kenwright and Levi' tried a different approach to the problem. They found that peak serum levels of rifampicin were raised by 86% if probenecid was given orally 30 min before the dose of rifampicin, and mean rifampicin serum levels at 4, 6, and 9 h were increased by about 100%. Since it seemed likely that the raised rifampicin levels were due to suppression of hepatic uptake there was the further possible advantage of achieving a reduction in the incidence of liver-function disturbance which rifampicin sometimes causes." In view of these findings, we decided to examine the effect of probenecid on rifampicin serum levels in patients receiving the drug alone and also in others receiving ethambutol and/or isoniazid. RIFAMPICIN
Group
t
Group la.-Six chronic bronchitic patients were studied to find out whether the peak serum-level in patients receiving rifampicin alone occurred at the same time after dosage as in patients receiving probenecid beforehand. Three of these patients were given 600 mg of rifampicin on the first trial day, and 2 g probenecid plus 300 mg rifampicin on the second trial day. The other three patients were given the regimens in the reverse order. Bloodfor rifampicin levels was taken at the time of the rifampicin dose, and at I, 2, 3, 4, and 6 h thereafter. Group lb.-To see whether rifampicin serum-levels altered as therapy was continued when the drug was given alone or with probenecid, a trial was carried out on twelve further patients. Three received 600 mg rifampicin daily for 4 weeks, and three received 300 mg rifampicin plus 2 g probenecid daily for 4 weeks. Serum-rifampicin levels were estimated on the first day and then each week for 4 weeks. Three patients received 600 mg rifampicin on day 1, 300 mg rifampicin plus 2 g probenecid on day 2, and then 600 mg rifampicin daily for 4 weeks; three received 600 mg rifampicin on day 1, followed by 300 mg rifampicin plus 2 g probenecid daily for 4 weeks. Serum-rifampicin levels were estimated on the first and second days of treatment, then weekly until 4 weeks after the first dose. Group 2 Group 2a.-Six patients received isoniazid 300 mg per day in addition to rifampicin or rifampicin plus probenecid. Three of these patients had rifampicin levels estimated over a 4-week period on the same lines as patients in group lb. The other three had rifampicin levels estimated on the first and second days of treatment and then fortnightly from the third to the thirteenth weekof treatment. Group 2b.-Five patients received ethambutol in a daily dosage of 15 mg/kg body-weight in addition to rifampicin or rifampicin plus probenecid. These patients had rifampicin levels estimated over a 13-week period as for patients in group 2a. Group 2c.-Fourteen patients received ethambutol in a daily dose of 15 mg/kg body-weight plus isoniazid 300 mg daily, in addition to rifampicin or rifampicin plus probenecid. TABLE I-SUMMARY OF NUMBERS OF PATIENTS RECEIVING THE VARIOIIS DOSAGES OF RIFAMPICIN
Patients and Methods Rifampicin was given orally 3t h after breakfast (approximately It h before lunch). No food was allowed between breakfast and the administration of rifampicin. Probenecid was given in a 2 g oral dose 30 min before the rifampicin. When rifampicin was given without probenecid, the dose was 600 mg; when it was given after probenecid the dose was 300 mg. Two groups of patients agreed to take part in the trial; all were adult males. Group-1 patients had reached a stable state after recovering from exacerbations of chronic bronchitis; group 2 consisted of patients being treated for pulmonary tuberculosis. In all patients, except those in group 1a (see below), serum-rifampicin levels were estimated on blood taken 2 h after the dose of rifampicin.
25, 1975
(R)
(P)
AND PROBENECID
Dosage schedule Patient group 1a Ib 2a 2b 2c Total
A
B
C
D
E
F
Total
3
3
..
..
..
..
3 2
3 I
2 1 7
3' 1 4 7
6 12 6 5 14
.. .. .. ..
.. .. .. ..
.. ..
.. ..
3
3
5
4
13
15
43
A~ B= C= D=
600 mg R day 1, 300 mg R + 2 g P day 2. 300 mg R + 2 g P day 1,600 mg R day 2. 600 mg R daily for 4 weeks. 300 mg R + 2 g P daily for 4 weeks. E = 600 mg R on day l , 300 IT £ R + 2 £ P day 2, thereafter 600 mg R daily for \3 weeks ('group Ib 4 weeks only). F = 600 mg R on day I, thereafter 300 mg R + 2 g P daily for \3 weeks ('gtoup Ib 4 weeks only).
DR KAN AND OTHERS: REFERENCEs-continued
5. Chang, H., Alter, B. P., Nathan, D. G. Proceedings of the First National Symposium on Sickle Cell Disease, Washington, D.C., 1974. 6. Kan Y. W., Valenti, C.~ Carnazza, V., Guidotti, R., Rieder, R. F. Lancet., 1974, i, 79. 7. Kan, Y. W., Golbus, M. S., Klein, P., Oozy, A. M. New Engl.J. Med. 1975, 292,1096. 8. Kan, Y. W., Nathan, D. G., Cividalli, G., Crookston, M. C. Blood, 1974, 43,411. 9. Bank, A., O'Donneli, J. V. Nature, 1969,222,295. 10. Wood, W. G., Stamatoyannopoulos, G.J. din. Invest. 1975,55,567.
TABLE II-MEAN SERUM-RIFAMPICIN LEVELS tN PATIENTS DAILY RECEIVING 600 mg RIFAMPICIN (R) OR 300 mg PLUS PROBENECID (P)
Mean serum Dose
600 mg R 300mgR+P
1
7
\3·1 10·7
14·3 4·6
rifampicin (~g/ml) on day:
14
21
28
\3·7 5·9
12·1 5·1
12 4·9
THE LANCET , OCTOBER
25,1975
793
TABL E III-RESULT S W IT H LONG-TE RM REGI MENS OF RIF AMPI CIN (R ) WITH OR WITHOUT PROB ENECID
(P)
Serum levels ( ~ glml) on: Dosage schedule"
Day I
Day 2
,
10·1 9·7 9·3±5 ·1
E
F .\ \ean±s .D·t
4·7 4·8 ±3 ·9
Week 3
Week '
Week 7
Week 9
Week II
Week 13
12·1 4 ·3
9·6 4· 7
10·' 4·9
11·4 5·6
11·4 ' ·3
6·8 3·8
tM ean ± s.D. for all 28 patients in groups I b and 2 = 1O· !±4·8 on day I and ' ·3±3 ·8 on day 2. "600 mg R on day I, 300 mg R + 2 g P on day 2, and 600 mg R (schedule E) or 300 mg R+P (schedule F) daily there after. TABLE IV-
SERUM I. EVEI. S OF RI FAMPI CI :-l (pg/ ml) IN PATI ENT S RECEI VING
600 mg OF
RIFAMPI CIN
Patien t
Dose
(R) O R 300 mg RIFAMPI CI N PL US 2 g
P ROBENEC ID
(P)
Time after dose (h)
no.
Day 2
Day I 0(24")
0
I
2
3
600 mg R day I. 300 mg R + 2 g P day 2
1 2 3
0 0 0
22 16·8 20·3
17·1 14·8 15
18·2 11·4 13-6
13·6 10·8 16·2
10·4 9·' 10
4·2 0·2 0
300 mgR +2g P day J. 600 mg R day 2
4 5 6
0 3-9t 0
1· 7 4·4 I
6·8 4 ·6 1·2
, ·5 3·2 3·3
4 ·2 3·6 4 ·4
3 12 ·6 6·8
0 0·3 15·4
4
6
I
2
3
4
6
10·' 12·4 3·2
9 ·2 7 ·6 9
6·1 4·2 6
4 3·2 5·2
3·' 2·3 2·2
16·' 17 18·9
9 ·8 18·7 22
8·' 16·' 11·7
6·9 11·8 9·9
7·8 8·8 9· 7
t False result du e \0 previous tet racycline thera py although th is was
• 24 h a fter Ist dose
stopped 24 h before rifampicin was given.
Rifampicin levels were estimated over a 13-week period as for pat ients in group 2a . The treatment received by the various groups is summarised in table I . Assay of RIfampicin Serum-levels of rifampicin were assayed microbiologicall y, as recommended by the manufacturers, using Staphylococcus lactis NCTC 8340 as the test organ ism. Patients' sera were separated and stored at - 20ce until assay. Tests were set up in 25 x25 cm plates which were incubated at 30"C instead of 37"C, since this makes the zones of inh ibition easier to read. Standard curves were constructed and corrections made for variations in the performance of standards during tests by the method of Grove and Randall," Prel iminary studies showed that the presence of ethambutol and/or isoniazid did not affect the microbiological assay of rifampicin .
Results Table II shows the geometric mean serum levels of rifampicin in patients receiving daily either 600 mg rifampicin or 300 mg rifampicin plus probenecid for 4 weeks (table I, group l b, schedules C and D). Apart from day 1 the serum levels in pat ients receiving rifampicin 300 mg plus probenecid were less than half those achieved in patients receiving 600 mg rifampicin da ily. Table III shows the geometric mean serum-rifampicin levels in patients receiving 600 mg rifampicin on the first day of treatment and 300 mg rifampicin plus probenecid on the second day, and then either 600 mg rifampicin (schedule E), or 300 mg rifampicin plus probenecid (schedule F) for 13 weeks. These patients also received isoniazid or ethambutol or both. Over the whole period of the trial the rifampicin levels in patients receiving 300 mg rifampicin plus probenecid were only about half those achieved in patients receiving 600 mg rifampicin daily. The decision to exam ine blood withdrawn 2 h after dosage was based on the finding! 4 that the peak serum level of rifampicin when taken fasting occurred at this time. However, the possibility that probenecid might influence the time of peak serum levels was investigated in
the patients in group la (table IV). In two of the patients who received 600 mg rifampicin on day 1 and 300 mg rifampicin plus 2 g probenecid on day 2 (schedule A) the peak serum level on day 1 was double that on day 2 (even although there was residual rifampicin present in the serum of case 1 24 h after the initial dose). Patient 4 also showed a peak serum level after 600 mg of rifampicin of more than double that with 300 mg plus probenecid. Cases 5 and 6 showed gross delay in rifampicin absorption following probenecid but not in the absence of this drug.
Discussion Kenwright and Levi! found a mean peak rifampicin serum level of 4·4 p.g/ml in volunteers given 300 mg rifampicin without probenecid. When 2 g probenecid was given half an hour before the 300 mg rifampicin, the mean serum level attained was 8·2 p.g/ml (86% higher ). We found that serum-rifampicin levels are not significantl y increased by the previous administration of probenecid. The mean concentration achieved in patients receiving 2 g probenecid half an hour before 300 mg rifampicin were only about half the mean in patients given 600 mg rifampicin without probenecid-and this was so whether the comparison was made over 2 days or up to 13 weeks and whether or not the rifampicin was accompanied by other antituberculosis drugs. In only three of twenty-eight patients given 600 mg rifampicin on day 1 and 300 mg rifampicin plus probenecid on day 2 did the serum-rifampicin level on day 2 not fall to about half that achieved on day 1. The three exceptions may ha ve been due to poor absorption or to peak levels at times other than those of blood withdrawal on day 1. It is interesting that Kenwright and Levi! excluded one pat ient from their study because he had delayed absorption with a peak at 6 h. This delay may be a feature of some patients when given probenecid, as suggested by the results with patients 5 and 6 in table IV, but there is a considerable variation in the pharmacokinetics of
794
THE LANCET, OCTOBER
rifampicin absorption between different individuals,' 6 and even in the same patient. 7 8 Nevertheless we have excluded very low serum levels in patients receiving probenecid from the analysis in tables II and III in case these levels were due to delay in absorption. We were surprised to find that in three of the patients noted in table IV the peak serum level occurred as early as 1 h after 600 mg of rifampicin (and in two of the three after rifampicin and probenecid). Our patients were not fasting but took the rifampicin h after a light breakfast and it may well be that this affected absorption but not (in four of the six patients in table IV) by delaying the peak nor, judging by the high mean serum levels reached, was the peak delayed in most of the patients in the main study. The results of this study indicate that if probenecid given before rifampicin does increase serum-rifampicin levels this effect is so uncommon and inconsistent that probenecid would have no place in routine rifampicin therapy.
3t
We thank P. Connell who did the antibiotic assays and Miss E. P. Laird for secretarial assistance. Requests for reprints should be addressed to R.
J. F.
REFERENCES
I. Kenwright, S., Levi, A. J. Lancet, 1973, ii, 1405.
2. Lees, A. W., Asgher, B., Hashem, M. A., Sinha, B. W. Br. J. Dis. Chest, 1970, 64, 90. 3. Grove, D. D., Randall, W. A. Assay Methods of Antibiotics: a Laboratory Manual; p. 15. New York, 1955. . 4. Dans, P. E., McGehee, R. F. jr., Wilcox, c., Finland, M. Am. J. med. Sci. 1970,259,120. 5. Roman, G., Malmborg, A.-S. Eur.J din. Pharmac. 1974,7, I. 6. Wardell, W. M., McQueen, E. G. N. Z. med.J. 1970,72,393. 7. Caneui, G., Diurovic, V., le Lirzin, M" Thibier, R., Lepeuple, A. Revue Tuberc. 1970,34,93. . 8. Siegler, D. 1., Burley, D. M., Bryant, M., Citron, K. M., Standen, S. M. Lancet, 1974, ii, 197.
DOWN SYNDROME AND THYROID FUNCTION IN ADULTS R. G. BAXTER F. 1. R. MARTIN KATHLEEN MYLES
R. G.
LARKINS PAULA HEYMA LYNNE RYAN
Queen Elizabeth Geriatric Centre, Ballarat, Victoria, and Departments of Endocrinology,Biochemistry, and Heematology, Royal Melbourne Hospital, Victoria, Australia
Thyroid function has been studied in 11 middle-aged and elderly subjects with proven Down syndrome. Unequivocal biochemical evidence of hypothyroidism was found in 6, and of thyrotoxicosis in 1. It is concluded that, in contrast to the situation in children with Down syndrome, thyroid dysfunction is exceedingly common in adults with the syndrome.
SummllYY
Introduction THERE have been several reports of an aSSOCiatIOn between Down syndrome and the occurrence of thyroid autoantibodies.>" and descriptions of individual patients with Down syndrome and overt hypothyroidism or thyrotoxicosis have appeared.·- 19 However, extensive studies of large numbers of children with Down syndrome have suggested that thyroid function is usually normal, with a very low prevalence
25,1975
of hypothyroidism or thyrotoxicosis, despite the high prevalence of thyroid autoantibodies.w
THE LANCET, OCTOBER
PROBENECID AND RIFAMPICIN SERUM LEVELS R. J. FALLON G. W. ALLAN W.
A. W.
LEES
J. SMITH F. TYRRELL
Department of Laboratory Medicine and Chest Department, Ruchill Hospital, Glasgow G20 9NB
Summary
Serum-levels of rifampicin were investigated in patients receiving rifampicin alone or with other antituberculosis drugs. 2 g of probenecid given 30 min before 300 mg of rifampicin did not result in raising serum levels to more than half those achieved with the standard 600 mg dose of rifampicin. Hence probenecid should not be used to reduce rifampicin dosage in antituberculosis therapy.
Introduction is not only the most effective companion for isoniazid in antituberculosis therapy, but also it has few troublesome side-effects and has the advantage of oral administration. It is, however, very expensive. To cut costs it has been given twice weekly instead of daily but this regimen, though effective, produces an unacceptably high incidence of allergic reactions. Kenwright and Levi' tried a different approach to the problem. They found that peak serum levels of rifampicin were raised by 86% if probenecid was given orally 30 min before the dose of rifampicin, and mean rifampicin serum levels at 4, 6, and 9 h were increased by about 100%. Since it seemed likely that the raised rifampicin levels were due to suppression of hepatic uptake there was the further possible advantage of achieving a reduction in the incidence of liver-function disturbance which rifampicin sometimes causes." In view of these findings, we decided to examine the effect of probenecid on rifampicin serum levels in patients receiving the drug alone and also in others receiving ethambutol and/or isoniazid. RIFAMPICIN
Group
t
Group la.-Six chronic bronchitic patients were studied to find out whether the peak serum-level in patients receiving rifampicin alone occurred at the same time after dosage as in patients receiving probenecid beforehand. Three of these patients were given 600 mg of rifampicin on the first trial day, and 2 g probenecid plus 300 mg rifampicin on the second trial day. The other three patients were given the regimens in the reverse order. Bloodfor rifampicin levels was taken at the time of the rifampicin dose, and at I, 2, 3, 4, and 6 h thereafter. Group lb.-To see whether rifampicin serum-levels altered as therapy was continued when the drug was given alone or with probenecid, a trial was carried out on twelve further patients. Three received 600 mg rifampicin daily for 4 weeks, and three received 300 mg rifampicin plus 2 g probenecid daily for 4 weeks. Serum-rifampicin levels were estimated on the first day and then each week for 4 weeks. Three patients received 600 mg rifampicin on day 1, 300 mg rifampicin plus 2 g probenecid on day 2, and then 600 mg rifampicin daily for 4 weeks; three received 600 mg rifampicin on day 1, followed by 300 mg rifampicin plus 2 g probenecid daily for 4 weeks. Serum-rifampicin levels were estimated on the first and second days of treatment, then weekly until 4 weeks after the first dose. Group 2 Group 2a.-Six patients received isoniazid 300 mg per day in addition to rifampicin or rifampicin plus probenecid. Three of these patients had rifampicin levels estimated over a 4-week period on the same lines as patients in group lb. The other three had rifampicin levels estimated on the first and second days of treatment and then fortnightly from the third to the thirteenth weekof treatment. Group 2b.-Five patients received ethambutol in a daily dosage of 15 mg/kg body-weight in addition to rifampicin or rifampicin plus probenecid. These patients had rifampicin levels estimated over a 13-week period as for patients in group 2a. Group 2c.-Fourteen patients received ethambutol in a daily dose of 15 mg/kg body-weight plus isoniazid 300 mg daily, in addition to rifampicin or rifampicin plus probenecid. TABLE I-SUMMARY OF NUMBERS OF PATIENTS RECEIVING THE VARIOIIS DOSAGES OF RIFAMPICIN
Patients and Methods Rifampicin was given orally 3t h after breakfast (approximately It h before lunch). No food was allowed between breakfast and the administration of rifampicin. Probenecid was given in a 2 g oral dose 30 min before the rifampicin. When rifampicin was given without probenecid, the dose was 600 mg; when it was given after probenecid the dose was 300 mg. Two groups of patients agreed to take part in the trial; all were adult males. Group-1 patients had reached a stable state after recovering from exacerbations of chronic bronchitis; group 2 consisted of patients being treated for pulmonary tuberculosis. In all patients, except those in group 1a (see below), serum-rifampicin levels were estimated on blood taken 2 h after the dose of rifampicin.
25, 1975
(R)
(P)
AND PROBENECID
Dosage schedule Patient group 1a Ib 2a 2b 2c Total
A
B
C
D
E
F
Total
3
3
..
..
..
..
3 2
3 I
2 1 7
3' 1 4 7
6 12 6 5 14
.. .. .. ..
.. .. .. ..
.. ..
.. ..
3
3
5
4
13
15
43
A~ B= C= D=
600 mg R day 1, 300 mg R + 2 g P day 2. 300 mg R + 2 g P day 1,600 mg R day 2. 600 mg R daily for 4 weeks. 300 mg R + 2 g P daily for 4 weeks. E = 600 mg R on day l , 300 IT £ R + 2 £ P day 2, thereafter 600 mg R daily for \3 weeks ('group Ib 4 weeks only). F = 600 mg R on day I, thereafter 300 mg R + 2 g P daily for \3 weeks ('gtoup Ib 4 weeks only).
DR KAN AND OTHERS: REFERENCEs-continued
5. Chang, H., Alter, B. P., Nathan, D. G. Proceedings of the First National Symposium on Sickle Cell Disease, Washington, D.C., 1974. 6. Kan Y. W., Valenti, C.~ Carnazza, V., Guidotti, R., Rieder, R. F. Lancet., 1974, i, 79. 7. Kan, Y. W., Golbus, M. S., Klein, P., Oozy, A. M. New Engl.J. Med. 1975, 292,1096. 8. Kan, Y. W., Nathan, D. G., Cividalli, G., Crookston, M. C. Blood, 1974, 43,411. 9. Bank, A., O'Donneli, J. V. Nature, 1969,222,295. 10. Wood, W. G., Stamatoyannopoulos, G.J. din. Invest. 1975,55,567.
TABLE II-MEAN SERUM-RIFAMPICIN LEVELS tN PATIENTS DAILY RECEIVING 600 mg RIFAMPICIN (R) OR 300 mg PLUS PROBENECID (P)
Mean serum Dose
600 mg R 300mgR+P
1
7
\3·1 10·7
14·3 4·6
rifampicin (~g/ml) on day:
14
21
28
\3·7 5·9
12·1 5·1
12 4·9
THE LANCET , OCTOBER
25,1975
793
TABL E III-RESULT S W IT H LONG-TE RM REGI MENS OF RIF AMPI CIN (R ) WITH OR WITHOUT PROB ENECID
(P)
Serum levels ( ~ glml) on: Dosage schedule"
Day I
Day 2
,
10·1 9·7 9·3±5 ·1
E
F .\ \ean±s .D·t
4·7 4·8 ±3 ·9
Week 3
Week '
Week 7
Week 9
Week II
Week 13
12·1 4 ·3
9·6 4· 7
10·' 4·9
11·4 5·6
11·4 ' ·3
6·8 3·8
tM ean ± s.D. for all 28 patients in groups I b and 2 = 1O· !±4·8 on day I and ' ·3±3 ·8 on day 2. "600 mg R on day I, 300 mg R + 2 g P on day 2, and 600 mg R (schedule E) or 300 mg R+P (schedule F) daily there after. TABLE IV-
SERUM I. EVEI. S OF RI FAMPI CI :-l (pg/ ml) IN PATI ENT S RECEI VING
600 mg OF
RIFAMPI CIN
Patien t
Dose
(R) O R 300 mg RIFAMPI CI N PL US 2 g
P ROBENEC ID
(P)
Time after dose (h)
no.
Day 2
Day I 0(24")
0
I
2
3
600 mg R day I. 300 mg R + 2 g P day 2
1 2 3
0 0 0
22 16·8 20·3
17·1 14·8 15
18·2 11·4 13-6
13·6 10·8 16·2
10·4 9·' 10
4·2 0·2 0
300 mgR +2g P day J. 600 mg R day 2
4 5 6
0 3-9t 0
1· 7 4·4 I
6·8 4 ·6 1·2
, ·5 3·2 3·3
4 ·2 3·6 4 ·4
3 12 ·6 6·8
0 0·3 15·4
4
6
I
2
3
4
6
10·' 12·4 3·2
9 ·2 7 ·6 9
6·1 4·2 6
4 3·2 5·2
3·' 2·3 2·2
16·' 17 18·9
9 ·8 18·7 22
8·' 16·' 11·7
6·9 11·8 9·9
7·8 8·8 9· 7
t False result du e \0 previous tet racycline thera py although th is was
• 24 h a fter Ist dose
stopped 24 h before rifampicin was given.
Rifampicin levels were estimated over a 13-week period as for pat ients in group 2a . The treatment received by the various groups is summarised in table I . Assay of RIfampicin Serum-levels of rifampicin were assayed microbiologicall y, as recommended by the manufacturers, using Staphylococcus lactis NCTC 8340 as the test organ ism. Patients' sera were separated and stored at - 20ce until assay. Tests were set up in 25 x25 cm plates which were incubated at 30"C instead of 37"C, since this makes the zones of inh ibition easier to read. Standard curves were constructed and corrections made for variations in the performance of standards during tests by the method of Grove and Randall," Prel iminary studies showed that the presence of ethambutol and/or isoniazid did not affect the microbiological assay of rifampicin .
Results Table II shows the geometric mean serum levels of rifampicin in patients receiving daily either 600 mg rifampicin or 300 mg rifampicin plus probenecid for 4 weeks (table I, group l b, schedules C and D). Apart from day 1 the serum levels in pat ients receiving rifampicin 300 mg plus probenecid were less than half those achieved in patients receiving 600 mg rifampicin da ily. Table III shows the geometric mean serum-rifampicin levels in patients receiving 600 mg rifampicin on the first day of treatment and 300 mg rifampicin plus probenecid on the second day, and then either 600 mg rifampicin (schedule E), or 300 mg rifampicin plus probenecid (schedule F) for 13 weeks. These patients also received isoniazid or ethambutol or both. Over the whole period of the trial the rifampicin levels in patients receiving 300 mg rifampicin plus probenecid were only about half those achieved in patients receiving 600 mg rifampicin daily. The decision to exam ine blood withdrawn 2 h after dosage was based on the finding! 4 that the peak serum level of rifampicin when taken fasting occurred at this time. However, the possibility that probenecid might influence the time of peak serum levels was investigated in
the patients in group la (table IV). In two of the patients who received 600 mg rifampicin on day 1 and 300 mg rifampicin plus 2 g probenecid on day 2 (schedule A) the peak serum level on day 1 was double that on day 2 (even although there was residual rifampicin present in the serum of case 1 24 h after the initial dose). Patient 4 also showed a peak serum level after 600 mg of rifampicin of more than double that with 300 mg plus probenecid. Cases 5 and 6 showed gross delay in rifampicin absorption following probenecid but not in the absence of this drug.
Discussion Kenwright and Levi! found a mean peak rifampicin serum level of 4·4 p.g/ml in volunteers given 300 mg rifampicin without probenecid. When 2 g probenecid was given half an hour before the 300 mg rifampicin, the mean serum level attained was 8·2 p.g/ml (86% higher ). We found that serum-rifampicin levels are not significantl y increased by the previous administration of probenecid. The mean concentration achieved in patients receiving 2 g probenecid half an hour before 300 mg rifampicin were only about half the mean in patients given 600 mg rifampicin without probenecid-and this was so whether the comparison was made over 2 days or up to 13 weeks and whether or not the rifampicin was accompanied by other antituberculosis drugs. In only three of twenty-eight patients given 600 mg rifampicin on day 1 and 300 mg rifampicin plus probenecid on day 2 did the serum-rifampicin level on day 2 not fall to about half that achieved on day 1. The three exceptions may ha ve been due to poor absorption or to peak levels at times other than those of blood withdrawal on day 1. It is interesting that Kenwright and Levi! excluded one pat ient from their study because he had delayed absorption with a peak at 6 h. This delay may be a feature of some patients when given probenecid, as suggested by the results with patients 5 and 6 in table IV, but there is a considerable variation in the pharmacokinetics of
794
THE LANCET, OCTOBER
rifampicin absorption between different individuals,' 6 and even in the same patient. 7 8 Nevertheless we have excluded very low serum levels in patients receiving probenecid from the analysis in tables II and III in case these levels were due to delay in absorption. We were surprised to find that in three of the patients noted in table IV the peak serum level occurred as early as 1 h after 600 mg of rifampicin (and in two of the three after rifampicin and probenecid). Our patients were not fasting but took the rifampicin h after a light breakfast and it may well be that this affected absorption but not (in four of the six patients in table IV) by delaying the peak nor, judging by the high mean serum levels reached, was the peak delayed in most of the patients in the main study. The results of this study indicate that if probenecid given before rifampicin does increase serum-rifampicin levels this effect is so uncommon and inconsistent that probenecid would have no place in routine rifampicin therapy.
3t
We thank P. Connell who did the antibiotic assays and Miss E. P. Laird for secretarial assistance. Requests for reprints should be addressed to R.
J. F.
REFERENCES
I. Kenwright, S., Levi, A. J. Lancet, 1973, ii, 1405.
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DOWN SYNDROME AND THYROID FUNCTION IN ADULTS R. G. BAXTER F. 1. R. MARTIN KATHLEEN MYLES
R. G.
LARKINS PAULA HEYMA LYNNE RYAN
Queen Elizabeth Geriatric Centre, Ballarat, Victoria, and Departments of Endocrinology,Biochemistry, and Heematology, Royal Melbourne Hospital, Victoria, Australia
Thyroid function has been studied in 11 middle-aged and elderly subjects with proven Down syndrome. Unequivocal biochemical evidence of hypothyroidism was found in 6, and of thyrotoxicosis in 1. It is concluded that, in contrast to the situation in children with Down syndrome, thyroid dysfunction is exceedingly common in adults with the syndrome.
SummllYY
Introduction THERE have been several reports of an aSSOCiatIOn between Down syndrome and the occurrence of thyroid autoantibodies.>" and descriptions of individual patients with Down syndrome and overt hypothyroidism or thyrotoxicosis have appeared.·- 19 However, extensive studies of large numbers of children with Down syndrome have suggested that thyroid function is usually normal, with a very low prevalence
25,1975
of hypothyroidism or thyrotoxicosis, despite the high prevalence of thyroid autoantibodies.w
