Jun 30, 1983 - Steady-state kinetics of SA (total and unbound), salicyluric acid (SUA), gentisic acid (GA), and clinical status were estimated weekly in 10 ...
Disposition of and clinical response to salicylates in patients with rheumatoid disease The disposition of salicylic acid (SA) and its metabolites and the clinical response to long-term aspirin treatment at varying doses were assessed in patients with rheumatoid disease. Steady-state kinetics of SA (total and unbound), salicyluric acid (SUA), gentisic acid (GA), and clinical status were estimated weekly in 10 patients with rheumatoid arthritis. Eight received a
soluble aspirin form and two received an enteric-coated form. The starting dose of aspirin in each patient was 1.8 gm (soluble) or 1.95 gm (enteric-coated) daily. Weekly increments in dose were made until a satisfactory clinical outcome was achieved. The final aspirin dose range was 3.6 to 8.1 gm daily, which resulted in mean steady-state plasma SA concentrations (Cp.) from 56 to 375 mg/I. Since the mean total Cp. increased approximately proportionately over the dose range, there was little change in total SA clearance. By contrast, increasing aspirin dosage resulted in decreased clearance and disproportionate increases in unbound SA (CpusA). The maximum velocity of conversion of SA to SUA (Vm) increased significantly, from 57.3 ± 11.7 mg/hr at an aspirin dose of 1.8 gm/day to 71.4 ± 19.4 mg/hr at the next highest dose (2.7 to 3.6 gm/day), with no further change with increasing dosage. Km ranged from 0.4 to 1.2 mg/1 to 17.2 for total CpsA. Renal clearance of SUA (C1,,,) ranged from 124 to 893 mllmin and correlated with creatinine clearance. Cl. ranged from 23 to 164 ml/mm, and CI. ranged from 0.1 to 17.1 ml/mm; neither correlated with creatinine clearance. The fraction of CpusuA ranged from 20% to 75% and correlated with the fraction of CpusA. There
for CpusA and from 5.5
was a significant improvement in the patients' clinical status with rising Cp.. Disposition of salicylate and metabolites does not appear to differ in patients with rheumatoid disease from
that in healthy subjects.
Michael Giinsberg, M.D., Felix Bochner, M.D., Garry Graham, Ph.D., Debra Imhoff, B.Sc., Glenda Parsons, B.Sp.Thy., and Bill Cham, Ph.D. Brisbane, Adelaide, and Sydney, Australia Departments of Rheumatology, Otolaryngology, and Medicine, Royal Brisbane Hospital, Brisbane, Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, and School of Physiology and Pharmacology, University of New South Wales, Sydney
Aspirin is still widely used at high doses in rheumatic disease. Dosage is controlled by the accumulation of its metabolite salicylic acid
Supported by the National Health and Medical Research Council. Received for publication June 30, 1983; accepted Dec. 21, 1983.
Reprint requests to: Professor F. Bochner, M.D., Department of Clinical and Experimental Pharmacology, The University of Adelaide, Adelaide, South Australia 5000, Australia.
(SA), which has a much longer t1/2 than aspirin23 and consequently accumulates more. For several years it has been known that the elimination kinetics of SA are complex because of its saturable binding to plasma proteins2' 7' 9' 27 and its pH-dependent excretion in urine.25 Also, capacity of two of its pathways of metabolism is limited.12' 13 More recently a further complexity was found, that the rate of formation of sali585
Clin. Pharmacol. Ther.
Gfinsberg et al.
586
May 1984
Fig. 1. Time course of Cps. The open symbols joined by the solid lines denote total CpsA; the closed symbols joined by the broken lines denote CpusA. A, Patient 1, who received soluble aspirin in a daily dose of 1.8 gm (o), 3.6 gm (o), 5.4 gm (L), or 7.2 gm (o). B, patient 9, who daily received enteric-coated aspirin, 1.95 gm (o), 3.9 gm (o), or 5.85 gm (h).
Table I. Subject data Age (yr)
Weight (kg)
M F
56
71
55
52
F
50
72.2
M M
69 90 104 62 52 51.1
48.6
Patient Sex 1
2 3
4
8
F
9
F
62 55 47 43 67 69
10
F
67
5
7
F F
6
Disease category
Daily aspirin dose before study (gm)
2.6-3.9 C
3.9 5.2 1.3-2.6 5.85 C
Other drugs Ibuprofen, gold, imipramine Gold Naproxen, penicillamine Dipyridamole Naproxen, azathioprine, prednisone Gold Naproxen, penicillamine Penicillamine, vitamin D, calcium, folic acid Naproxen, gold, furosemide, digoxin, doxepin, potassium
2.6-3.9
C = classical rheumatoid arthritis; D = definite rheumatoid arthritis.
cyluric acid (SUA), the glycine conjugate of salicylate, is inducible.' Furst et al.' found in healthy subjects that total SA clearance did not greatly change with increasing doses because of simultaneous saturation of binding to plasma proteins, but they did not determine whether continuing induction of SUA contributed to the constant clearance of SA. Our study was designed to examine SA kinetics during long-term treatment in patients with rheumatoid arthritis. A special aim was to de-
termine whether the formation of SUA is further induced as the dosage of aspirin is increased and to establish whether the interesting results of Furst et al.' could in part be explained by continuing induction of SUA formation. Responses of patients to different dosage regimens of aspirin were examined at the same time. A soluble aspirin form was used so that the drug would be absorbed reliably and a range of plasma concentrations (Cp) of SA would be produced; thus kinetic parameters over an interdosing interval
Salicylate disposition and response in rheumatoid disease
Volume 35
587
Number 5
BO
240
60
E
Ao
--
160
11--
20
BO
--
-----
BO
mean Cp54
160
mg/I
240
0
2
4
ASPIRIN DOSE
6
giday
Fig. 2. Relationship between total SA clearance and mean total Cps, (left panel) and mean total CpsA and daily aspirin dose (right panel). refers to patient 9, o to patient 3, to patient 8, and o to patient 5.
could be satisfactorily derived. These results were compared with those after an entericcoated dosage form that results in relatively constant Cp during a dosage interval. Methods
Our subjects were 10 patients with classical or definite rheumatoid arthritis' (Table I). Aspirin was stopped for at least 3 days before the study in the six patients who had been receiving regular aspirin. They were given acetaminophen as required for pain relief. All other medication, including other anti-inflammatory drugs, was continued and doses were not changed throughout the study. Before starting aspirin and weekly thereafter, each patient underwent assessment of disease severity," hearing and cochlear function, and hematologic and biochemical status. Each patient was asked to keep an accurate record of symptoms (articular and those attributed to adverse effects of aspirin) and how much acetaminophen was needed for analgesia. Each patient was admitted to the hospital on the day of each study procedure. Eight of 10 patients received a soluble aspirin product, Asproclear (Nicholas); each tablet contained 300 mg aspirin, 400 mg anhydrous citric acid, and 600 mg sodium bicarbonate. Patients 9 and 10 were given enteric-coated aspirin (Ecotrin; Smith, Kline & French); each tablet contained 650 mg aspirin. The starting dose of aspirin was 600 mg
(soluble) or 650 mg (enteric-coated) at 8-hr intervals (6:00 A.M., 2:00 P.M., 10:00 P.m.) in each patient. The aspirin dose was increased at weekly intervals by increments of 0.9 to 1.8 gm daily. Ultimately, the number of separate studies for each patient ranged from 2 to 5, and the maximum daily aspirin dose ranged from 3.6 to 8.1 gm. A kinetic study over an interdosing interval was performed starting at 2:00 P.M. at the end of each week of treatment. Venous blood was drawn before and hourly after aspirin through a Teflon indwelling catheter from an antecubital fossa vein. Urine was collected hourly and the volume and pH were measured immediately. Plasma and urine samples were stored frozen at 20° for analysis of salicylates and creatinine. The articular index of Ritchie et al." was completed by the same observer on each occasion and recorded as a numeric score. The audiologic tests consisted of pure tone audiometry speech discrimination with lists of phonetically balanced words and two tests of cochlear function, the short increment sensitivity index (SISI)" and a test of loudness recruitment.' A Grason Stadler Audiometer 1702 was used with Telektronics TDHSO headphones to obtain pure tone thresholds and SISI scores. A Sony 3 head tape recorder was used for presentation of the lists of phonetically balanced words. The Metz test was administered by the use of a Peters AP62 impedance meter.
588
aim
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PharmacoL Ther. May 1984
Table II. Some parameters with varying aspirin doses Mean
Patient No. 1
Dose aspirin (gm/day) 1.8
3.6 5.4 7.2 2 3
4
6
7
10
CpusA
(mgIl)
6 16
28 75
3 8
0 4
115 139 41 95
16
4
1.8
0 0 0 0 0
1.8
21 19
12
3.6 5.4
0 0 0 0
1.8
2
3.6 5.4 7.2
0
1.8
1.8
2
0 2
29 57 79
29 3
9 2
6
clearance (ml/mm)
SA
Total
Unbound
Renal
35
332 249 133
3.9 7.6 11.7 11.9
313 202
10.5
26 25 28 23 20 33 25
10 14 22
24
26 50 92
2
37 29
129
16
115 126
11
37
56 20 68 93 166
4
9 1
21
23
21 19
88
4 9
52
2
62 37 ao 30 48 24 25 37
6 8
16
51
20 80 96 26
2 12 18 10
31
0
61 111 153
1
172
22 39 50
26 25 25
89
18
3.9 5.85
0 0 0
152
40 59
12 13 15
1.95
2
3.9
0
4.5 1.8 3.6 5.4 7.2 8.1
9
Cps,.
(mgll)
10
3.6 8
AP* needed
1.8
2.7 3.6 4.5 5
steady-state
3.6 2.7 3.6 4.5 5.4
Mean steady-state
Extra
1.95
4 0 14 9 2
208 114 375
4
17
133
9 6
181
444 238 193 166 132 497 363 209 146
988 493 304 749 432 484 305 465 162 131
232 184 132 100 113
59 52
4.0 6.4 3.9 6.5 5.6 4.8 2.5 1.5
2.8 3.0 9.5 17.1
14.4 4.1 11.0
9.6 7.7 7.7 13.3 10.4
3.9 10.6 13.1 12.1 14.1
4.3
53 62
1.6 0.1 1.3
16
0.4
Mean urinary pH 6.4 7.1
7.6 7.0 6.7 7.5 7.1
7.0 7.2 7.3 7.2 7.0 6.5 6.8
6.6 6.3 7.0 7.1
6.5
6.9 7.3
7.0 7.4 7.4 7.8 7.4 7.6 7.6 7.8 7.7 6.8 6.4 5.7 6.0 5.4
*AP = acetaminophen.
SA, SUA, and gentisic acid (GA) were measured in plasma,' urine,' and ultrafiltrate of plasmal by HPLC. Urinary creatinine was measured by the method of Yatzidis28 and plasma creatinine by an automated method (Technicon). Total body clearance of SA from plasma and total body clearance of unbound drug were calculated from the quotient dose/of8Cpdt, the integral as estimated by trapezoidal rule. Renal clearances (Cl) of SA, SUA, and GA were de-
rived from the quotient IAeo_s/of8Cpdt, where Ae and Cp refer to the excretion and plasma concentrations of SA, SUA, or GA. The mean steady-state concentrations of total (Cp) and unbound (Cpu) SA were calculated from the quotient of8 (Cpdt/8). The Michaelis-Menten constants Vm (maximal velocity of conversion of SA to SUA) and Km were determined by the method of Wilkinson26 from the relationship GpusA)/(K, + CpusA). This relaCPsup = (Vm
Salicylate disposition and response in rheumatoid disease
Volume 35 Number 5
589
1000
750
50
500
250
20
a
-a-
20
'ea"
60
40
CPSAlurtbound
mg/I
2
4
ASPIRIN DOSE
g/day
Fig. 3. Relationship between unbound SA clearance and mean CpusA (left panel) and mean CpusA and daily aspirin dose (right panel). Symbols are as in Fig. 2.
tionship gave the Km in terms of Cpu The Km value expressed as total Cp was then determined from the regression line between percentage unbound and total Cps,. In the patients, CDSUA fluctuated little over the 8-hr study period. Therefore, a correction factor' to account for changes in CpSUA was not used. The clinical response as measured by the index of Ritchie et al.' was correlated against the mean total Cps, by analysis of variance (unbalanced data). For this purpose the mean Ritchie et al. index scores for all the patients were categorized according to the mean Cp, range groups of 0 (pretreatment), 0 to 60, 60 to 120, and 120 to 180 mg//. All data are X ± SD unless otherwise indicated. Specific contrasts were made by paired t tests after calculating the mean Ritchie index when there were multiple scores within any range of Cps, for a particular patient. These statistical analyses were made on data from patients treated with the soluble tablets only, since these Cps, patterns during a dose interval differed from those in patients treated with the enteric-coated tablets. .
Results
During treatment with the soluble tablets, Cps, varied considerably over the 8-hr dosage intervals. At the lowest dosage of aspirin (1.8 gm daily), maximal total (bound and unbound) Cps, was up to 600% the minimal concentrations (Fig. 1, A). The fluctuation in Cp decreased as the dosage increased, and at 7.2 gm
aspirin daily the maximal range of total CPSA was 200% (Fig. 1, A). Cpus, fluctuated over a slightly greater range over the dosage intervals (Fig. 1, A). With the soluble tablets, Cps, just before the dose of aspirin was frequently greater than Cps 8 hr later (Fig. 1, A). The mean total Cps, rose approximately proportionately over the range of doses used (Fig. 2). Consequently, there was little change in the total plasma SA clearance (Fig. 2, Table II), particularly at doses above 3.6 gm daily or at Cps, above 50 mg//. In contrast, Cpu, increased disproportionately as daily aspirin dosage increased (Fig. 3; Table II). Correspondingly, unbound SA clearance decreased with increasing dosage of aspirin and increasing Cps, in almost every case (Fig. 3; Table II). There was very little fluctuation in the time course of Cps, (bound or unbound) after enteric-coated aspirin at any of the doses (Fig. 1, B). In the eight patients who took the soluble tablets, there was a consistent rise in Vm for the formation of SUA from SA after increasing the aspirin dose from 1.8 gm daily (Vm range = 46 to 82 mg/hr; X = 57.3 ± 11.7 mg/hr) to the next increment (2.7 or 3.6 gm daily; Vm range = 54 to 112 mg/hr; X = 71.4 ± 19.4 mg /hr) (t = 4.9; P < 0.005) with no significant change after further increases in dosage (Table III). Km values could be calculated only after the lowest dose of aspirin (1.8 gm daily) because Cps, values after higher doses were considerably in excess of Km .1
590
Giinsberg et al.
Clin. Pharmacy!. Ther. May 1984
Table III. Michaelis-Menten constants
1000
Patient
Aspirin dose
No.
(gm)
750
500
Vm
unbound* (mg/hr)
unboundt
totalf
Ong10
(mg/1)
82 112 110 118
1.2
17.2
47 58 46 53 55 49 47 59 67 66 85 58 79 99 63 80 82 98 54 68
0.6
13.8
0.5
9.3
0.4
11.0
0.4
5.5
0.5
7.2
0.5
8.9
0.9
9.8
1.8
250
100 CREATININE
200
300
CLEARANCE
'
400
3.6 5.4 7.2
500
2
ml Imin
Fig. 4. Relationships between Cls.A (s), Cl,A (o), and creatinine clearance. Asterisks refer to clearances in patient 5, whose creatinine clearance values were consistently very high.
3
1.8
2.7 3.6 4.5 5.4 4
1.8
2.7 3.6 4.5
=
asuA ranged from 124 to 893 ml/min (5? 382 ± 192 ml/min) and correlated with creatinine clearance (r = 0.85; P < 0.001) (Fig. 4). The determination of CIGA could be measured only at the higher dose levels of aspirin, when CNA was sufficiently high to be measured accurately. CIG, ranged from 23 to 164 ml/min (.7 = 64 ± 40 ml/min) and there was no correlation between C1G, and creatinine clearance (Fig. 4). For all the patients, Cls, ranged from 0.1 to 17.1 ml/min (X = 7.2 ± 4.6 ml/min). In the eight patients who received soluble aspirin, total SA clearance ranged from 1.5 to 17.1 ml/min = 8.2 ± 4.2 ml/min). There was no correlation between Cls, and creatinine clearance. Mean urinary pH at the 1.8-gm soluble aspirin dose was 6.8 ± 0.4, and this rose to 7.4 ± 0.2 at 5.4 gm daily. There was a trend in the patients receiving soluble aspirin for to rise with increasing dosage and urinary pH. In the two patients who received entericwere coated aspirin, the urinary pH and considerably lower than after the soluble preparation (Table II). CpusuA were measurable only after the higher doses of aspirin. The fraction of CpusuA ranged from 20% to 75% and correlated (r = 0.73; P < 0.001) with the proportion of
1.8
3.6
5
1.8
3.6 5.4 6
1.8
3.6 5.4 7.2 7
1.8
3.6 8
4.5 1.8
3.6 5.4 7.2 8.1
61
49 54 74 85 75
*Maximum velocity of conversion of unbound SA to SUA.
tExpressed as CpusA. *Expressed as total CPsA.
Cl
Cl
CPU. The articular index of Ritchie et al. improved in nine of the 10 patients as the dose of aspirin rose (Table IV). In one patient (No. 8), the Ritchie index during five different dosage periods was higher than the pretreatment score, but the pretreatment score had been low, which indicated relatively inactive disease. There was a
significant improvement during treatment with aspirin and a clear relationship between response and CpsA could be detected (Table IV). There was no difference between control and response at CpsA values of 0 to 60 mg//, but there was significant improvement at the higher CpsA values. Extra acetaminophen requirements diminished with increasing aspirin dosage (Table II). There were no reported adverse effects and no tinnitus was reported. Hearing loss of 30 db at 2 KHz was recorded in patient 10 only; she achieved the highest mean total and unbound CNA. Over the course of the study there was a fall in the hemoglobin concentration of from 0.5 to 2.1 gm/di in six of the 10 patients; in three patients the hemoglobin concen-
Salicylate disposition and response in rheumatoid disease
Volume 35 Number 5
Table IV. Statistical analyses for Ritchie index vs mean soluble aspirin
CPSA (Mg I l) for
591
patients receiving
Ritchie index
Patient No.
Pretest (0 mg/1)
0-60 Ingll
60-120 mgll
120-180 mgll
17 17 7 12
16
14
12
1
21
17
2
24
3
4
13 19
22 7
5
33
22
6
16
7 8
25 9
18 18
± SD
20 ± 7.3
21
24 12
14
17.4
_±
6 11
5
14.7
Lf
11
5.3
11.2 ± 3.6
Analysis of variance: DF = 7, F = 22.13, P = 0.0003; adjusted, DF = 3, F = 5.6, P = 0.02. Paired t test: 0 mg/U0-60 mg//, P> 0.05; 0 mg///60-120 mg/I, P < 0.04; 0 mg///120-180 mg//, P = 0.05; 60-120 mg///120-180 mg//, P = 0.009.
trations were unchanged and in one patient it rose by 0.5 gm/d1.
Discussion There was a wide range of V. values, similar and in to that described in healthy subjects' of SA to SUA conversion patients.' The V. of increased when aspirin dosage increased from 1.8 to 2.7 or 3.6 gm daily, which indicates that induction of SUA formation is either dose dependent or is not complete within 7 days of starting treatment. It has been stated' that continued induction of SUA was the most probable reason for a fall in Cps, over several weeks of unchanged aspirin dosage .17 In our study, however, the mean rise (24%) in V. as the aspirin dose rose from 1.8 to 2.7 or 3.6 gm daily was relatively small. The large interindividual variations in Vrn were not reflected in correspondingly large intersubject differences in mean Cp in the eight patients receiving soluble aspirin. Apart from patient 5, there was little intersubject difference in mean Cps, at any was higher at dose rate. In most patients the higher doses. Consequently, the intersubject variations in V. had a relatively small effect on the total clearance of SA, particularly at the higher doses of aspirin. Although the major pathways of SA elimination are saturable," binding of SA to plasma proteins is also saturable.2. 7' 9' 27 Furst et al.9
Cl
found that total Cp increased approximately in proportion to aspirin dosage, while Cpu rose disproportionately. Our data are consistent with their interesting observations on SA accumulation in healthy subjects. Although plasma clearance of SA need not be constant over a dosage interval because of saturable kinetics, we observed approximately similar total clearance of SA at mean Cp values in the range of 50 to 170 mg//, whereas Furst et al.9 observed this to occur at concentrations above 100 mg//. The difference between their results and ours probably results from higher urinary pH and Cls, in our study. The small changes in V. in the patients over several weeks of aspirin treatment indicate that constant total plasma clearance of SA is not primarily because of continuing or dose-dependent induction of SUA formation. The mean clearances of SUA and GA were of the same order as those in healthy subjects, but the range of clearances was greater in our study. The body weights, ages, and renal function in the patients were variable, and these interpatient differences are probably responsible for the variable clearances. The variations in creatinine clearances from week to week in the same patient may relate to problems encountered with accurate urine collections from relatively incapacitated patients. It has been reported" that creatinine clearance is decreased by aspirin, but
592
Giinsberg et al.
Clin. Pharmacol. Ther. May 1984
any effect is temporary and returns to pretreatment levels during continued treatment.3 In our study, only patient No. 3 had any consistent decline in creatinine clearance with increasing aspirin dosage. The soluble preparation did not cause hearing loss or tinnitus. This is not surprising, since only one patient (No. 10) had mean Cps., above 200 mg// (No. 10 had a mean CPsA of 375 mg/I). Diminished hearing ability has been associated with above 200 mg//.13 In many cases, CpsA values at the beginning of the dosing interval were higher than at the end. At steady state, these CpsA values should be equal. The patients were hospitalized only on the day of each study period and it may be that the difference between trough levels resulted from inaccurate dosage times before the study. Diurnal variation in the metabolism of SA, however, has been described13 and could be responsible for these differences. Our study has yielded for the first time in patients results relating to SUA plasma protein binding. The correlation between the fractions of unbound SUA and SA indicate that SUA and SA may share a common binding site. Further in vitro work is necessary to clarify the plasma protein binding of SUA by itself and in the presence of varying CpsA . It is not likely that SUA protein binding has any significant effect on the plasma protein binding and clearance of SA, since SUA is present in much lower concentrations in plasma than is SA and the percentage binding of SUA after aspirin is less than that of SA. It is widely stated that the therapeutic range of CpsA is 150 to 300 mg//." For example, on stopping treatment with benorylate, exacerbation of disease activity was greater in patients in whom CpsA above 150 mg// had been reached than in those with lower CpsA.° There are, however, few other published data relating CpsA to suppression of the inflammation of rheumatoid arthritis, although there is good evidence that CpsA in the range of 300 to 400 mg// is required to suppress the manifestations of rheumatic fever in children.2° In our study, mean CpsA was generally below 150 mg//, but improvement in the Ritchie index was still observed. Although
Cp
peak CpsA values were higher, significant activity at these low mean Cps, values is interesting. Further work is required to define the therapeutic range of CNA in rheumatoid arthritis. While therapeutic activity increased over the range of CpsA in our study, it remains to be seen whether activity is further increased at higher concentrations. Studies will need to be done with preparations other than the soluble formulation used in this study. Although well tolerated, the soluble tablets produced relatively low CNA levels because of the higher urinary pH and high excretion of unchanged SA.
References Bochner F, Graham GG, Cham BE, Imhoff DM, Haavisto TM: Salicylate metabolite kinetics after several salicylates. CLIN PHARMACOL THER 30:266-275, 1981. Borga 0, Odar-Cederlof I, Ringsberger V, Norlin A: Protein binding of salicylate in uremic and normal plasma. CLIN PHARMACOL THER 20: 464-475, 1976. Burry HC, Dieppe PA: Apparent reduction of endogenous creatinine clearance by salicylate treatment. Br Med J 2:16-17, 1976. Cham BE, Bochner F, Imhoff DM, Johns D, Rowland M: Simultaneous liquid-chromatographic quantitation of salicylic acid, salicyluric acid and gentisic acid in urine. Clin Chem 26:111-114, 1980. Cham BE, Johns D, Bochner F, Imhoff DM, Rowland M: Simultaneous liquid-chromatographic quantitation of salicylic acid, salicyluric acid, and gentisic acid in plasma. Clin Chem 25:1420-1425, 1979. Champion GD, Day RO, Paull PD, Graham GG, Owen MS, Haski AL, Hills L: Clinical pharmacology and efficacy of benorylate in patients with rheumatoid arthritis. Aust NZ J Med 8:2228, 1978. Ekstrand R, Alvan G, Borga 0: Concentration dependent plasma protein binding of salicylate in rheumatoid patients. Clin Pharmacokinet 4: 137-143, 1979. Furst DE, Gupta N, Paulus HE: Salicylate metabolism in twins. Evidence suggesting a genetic influence and induction of salicylurate formation. J Clin Invest 60:32-42, 1977. Furst DE, Tozer TN, Melmom KL: Salicylate clearance, the resultant of protein binding and metabolism. CLIN PHARMACOL THER 26:380389, 1979. Graham G, Champion GD, Day RO, Haavisto TM, Paull PD: The pharmacokinetics of salicy-
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late in patients with rheumatoid arthritis. Clin Exp Pharmacol Physiol 6:194, 1979. Jerger J, Shedd JL, Harford E: On the detection of extremely small changes in sound intensity. Arch Otolaryngol 69:200-211, 1959. Levy G, Amsel LP, Elliott HC: Kinetics of salicyluric acid elimination in man. J Pharm Sci 58:827-829, 1969. Levy G, Tsuchiya T, Amsel LP: Limited capacity for salicylphenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man. CLIN PHARMACOL THER 13: 258-268, 1972. Mandelli M, Tognoni G: Monitoring plasma concentrations of salicylate. Clin Pharmacokinet 5:424-440, 1980. Markiewicz A, Semenowicz K: Time dependent changes in the pharmacokinetics of aspirin. Int J Clin Pharmacol Biopharm 17:409-411, 1979. Metz 0: Threshold of reflex contractions of muscles in the middle ear and loudness recruitment. Arch Otolaryngol 55:536-543, 1952. Muller FO, Hundt HKL, De Kock AC: Decreased steady-state salicylic acid plasma levels associated with chronic aspirin ingestion. Curr Med Res Opin 3:417-422, 1975. Myers EN, Bernstein JM, Fostiropolous G: Salicylate ototoxicity: A clinical study. N Engl J Med 273:587-590, 1965. Plotz P, Kimberly R, Gill JR Jr: Effect of salicylates on creatinine clearance. Br Med J 14:421422, 1976.
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Reid J: Does sodium salicylate cure rheumatic fever? Q J Med 17:139-151, 1948. Ritchie DM, Boyle JA, McInnes JM, Jasani MK, Dalakos TG, Grieveson P, Buchanan WW: Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med 37:393-406, 1968. Ropes MW, Bennett GA, Lobb S, Jacox R, Jessar RA: Diagnostic criteria for rheumatoid arthritis. Ann Rheum Dis 18:49-53, 1959. Rowland M, Riegelman S: Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous administration in man. J Pharm Sci 57:1313-1319, 1968. Rumble RH, Brooks PM, Roberts MS: Metabolism of salicylate during chronic aspirin therapy. Br J Clin Pharmacol 9:41-45, 1980. Smith PK, Gleason HL, Stoll CG, Ogorzalek S: Studies on the pharmacology of salicylates. J Pharmacol Exp Ther 87:237-255, 1946. Wilkinson ON: Statistical estimations in enzyme kinetics. Biochem J 80:324-332, 1961. Wosilait WD: Theoretical analysis of the binding of salicylate by human serum albumin: The relationship between free and bound drug and therapeutic levels. Eur J Clin Pharmacol 9:285-290, 1976. Yatzidis H: New method for direct determination of "true" creatinine. Clin Chem 20:1131-1134, 1974.
