Salicylate availability from salsalate (SSA) and aspirin (ASA) was examined in six rheumatoid arthritis patients in a multiple-dose double-blind crossover study. Doses contained equimolar amounts of salicylic acid. After initial ASA treatment to achieve therapeutic salicylate levels (150 to 300 micrograms/ml) the patients received equimolar doses of SSA or ASA. When steady state was achieved patients were hospitalized, and blood and urine specimens were obtained during three dosing intervals and during the washout period that followed. Thereafter, patients were placed on the alternate medication for at least a week and the in-hospital pattern was repeated. Despite insignificant differences in absorption of the formulations, as measured by urinary salicylate recovery, the plasma salicylic acid AUC was lower after SSA. Evidence indicates that this apparent lower availability of salicylate from SSA is due to incomplete hydrolysis to salicylic acid, the unhydrolyzed SSA being excreted mainly as glucuronide conjugates.

The kinetic interaction between salicylate and naproxen was investigated in 25 rheumatoid arthritis patients. Kinetic interactions were tested in serum after patients had been on each drug regimen for 1 month. Salicylate decreased serum naproxen concentration from 89.5 mg/liter to 65.9 mg/liter (P < 0.001) and increased serum naproxen clearance by 56%. Naproxen had minimal effect on serum salicylate concentrations.The pharmacokinetic interaction between salicylates (usually aspirin) and nonsteroidal antiinflammatory drugs (NSAIDs) has been investigated in single or short-term studies using normal volunteers (1-6). Salicylates decreased the area under the time-versusconcentration curve (AUC) of ketoprofen, isoxicam, ibuprofen, indomethacin, fenoprofen, and diclofenac by 8 4 8 % . In the only study of the kinetic interaction between naproxen and salicylate, 8 normal subjects were given single doses, and the AUC of naproxen was decreased by 16% (7). The majority of these drug-drug interaction studies are conducted using healthy subjects. The only study of NSAID-salicylate kinetic interaction in rheumatoid arthritis (RA) patients was an investigation of the interaction between

Previous studies of combinations of nonsteroidal drugs used in the treatment of rheumatoid arthritis (RA) have yielded conflicting results. We used standard methods to measure disease activity and high pressure liquid chromatography to measure plasma drug concentrations. We used doses of choline magnesium trisalicylate, adjusted to achieve therapeutic serum salicylate concentrations, and naproxen in a randomized, double‐blind, placebo‐controlled cross‐over study of full dose trisalicylate (CMT), full dose naproxen (N), full dose of both (CMT‐N), and half dose of both (cmt‐n) to examine their relative efficacy and toxicity in treating RA. CMT‐N was statistically superior to all other treatments in only 1 of 12 efficacy variables, but was equal to N and better than CMT or cmt‐n for 7 variables. There were minimal differences among treatments for the other 4 efficacy variables. The mean percentage difference for the efficacy variables between CMT‐N and N was 3%, between CMT‐N and CMT was 10.6%, and between CMT‐N and cmt‐n was 10.5%. Thirteen percent of patients manifested toxic reactions during the initial open dose‐adjustment salicylate run‐in phase. During the double‐blind phases of the study, CMT‐N was more toxic than N, CMT, or cmt‐n (7.5% versus 3.4%, 1.8%, and 3.7%, respectively). Tinnitus was more common when full‐dose CMT was used; N (N or CMT‐N) was associated with increased skin toxicity. Gastrointestinal complaints were equally common with all regimens. CMT‐N, although sometimes statistically superior to CMT, N, or cmt‐n, showed no clinically important additive or synergistic effect versus N or CMT alone.

When the total daily drug dose was individualized to produce a steady-state serum salicylate concentration between 20 and 35 mg/dl, clinically acceptable fluctuations of serum concentrations occurred during both twice daily and three times daily administration. In 6 rheumatoid arthritis patients receiving choline magnesium trisalicylate, mean steady-state serum levels were the same, and the ranges of hourly mean concentrations during 8 and 12 hour dosage intervals were 19 to 27 mg/dl and 17 to 30 mg/dl, respectively. Changing the dosing interval from 8 to 12 hours required a 50% increase in the fractional doses, but resulted in an increase of only 3 mg/dl in mean peak concentration and a decrease of 1 mg/dl in mean minimum concentration.Salicylates are among the most effective antiinflammatory drugs used in the treatment of rheumatoid arthritis. At the serum concentrations recommended, salicylate serum half-life is prolonged (l,2). It is, therefore, theoretically possible to administer salicy- late at infrequent intervals in large fractions of the total daily dose.We studied two such regimens in which salicylate was administered at 8 and at 12 hour intervals to hospitalized patients with active rheumatoid arthritis. The hourly variation in steady-state salicylate concentration was measured. Choline magnesium trisalicylate (CMT) was used as the salicylate source since it may have fewer adverse effects on the gastrointestinal tract than aspirin, as judged by chromium-tagged red blood cell loss (3) and by endoscopic evaluation (4). MATERIALS AND METHODSCholine magnesium trisalicylate was administered to 6 patients, 3 men and 3 women ranging in age from 24 to 57. All had active classic or definite rheumatoid arthritis (according to ARA criteria). None had clinically important renal, hepatic. or gastrointestinal disease as judged by history, physical examination, serum creatinine, urinalysis, SGOT. alkaline phosphatase. bilirubin. and LDH. Their characteristics are noted in Table I .During an initial outpatient phase of about 6 weeks. each patient's total daily dose of CMT was individualized by trial and error to achieve serum salicylate concentrations between 20 and 35 mg/dl at steady-state.After a minimum of 7 days on the selected dose, patients were hospitalized for 10 days at the Clinical Research Center, Center for Health Sciences, Los Angleles, California. The total daily dose was divided into three fractions and administered at 8 hour intervals for 5 days; the regimen was then changed so that two fractional doses were administered at I2 hour intervals for 5 days. The same total daily dose was used