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Twenty patients with definite or classical rheumatoid arthritis entered and completed a sequential study of placebo for 1 week, oral indomethacin 25 mg 3 times a day for 3 weeks, and oral indomethacin 25 mg 3 times a day plus 100 mg indomethacin suppository at night for 3 weeks. Twelve of the patients had previously been classified as responders and eight as nonresponders to indomethacin by an independent assessor. At the end of each period patients were assessed by a blind observer for duration of morning stiffness, pain score, digital joint size, grip strength, articular index, analgesic tablet usage, and the patient's own overall global assessment and comparative global assessment. In 8 of the 9 tests used responders improved on indomethacin in comparison with placebo, while nonresponders did not improve. There were no significant differences between responders and nonresponders in the plasma half-life, plasma clearance of indomethacin, protein binding of indomethacin, or urinary excretion of free or conjugated indomethacin. There were no significant differences between responders and nonresponders in the urinary excretion of 7HDPA or in the platelet aggregation or platelet malonyldialdehyde production tests. In responders there was a significant positive correlation between the plasma indomethacin concentration (r=0·44, P

In 6 patients anticoagulated with warfarin, nicoumalone, or phenindione the addition of cimetidine prolonged the prothrombin-time (PT) by a mean of 12·6 s (range 5-23 s). In 7 volunteers taking daily subtherapeutic doses of warfarin the addition of cimetidine increased the PT from 19·4 to 22·9 s and the plasma-warfarin concentration from 0·96 to 1·76 μg/ml. Cimetidine reduced the single-dose clearance of warfarin and antipyrine. The basis of the interaction between cimetidine and oral anticoagulants is probably inhibition of drug metabolism. Care should be exercised in concomitant therapy.

Twenty-one patients with rheumatoid arthritis were given indomethacin 25 mg t.i.d. by mouth for 3 weeks followed by indomethacin 25 mg t.i.d. plus a 100 mg suppository at night, after a 5-day period on placebo capsules. The mean (±S.E.) 24-hour creatinine clearance was 57.8 ± 5.7 ml/min in the placebo period and was not significantly altered during indomethacin therapy, 53.1 ± 5.5 ml/min in the oral period and 56.6 ± 6.4 ml/min in the oral plus suppository period (P > 0.1). In 6 volunteers, duplicate 2-hour creatinine clearances were performed after a single oral dose of 50 mg indomethacin. After placebo capsules the mean creatinine clearance was 133.7 ± 9.5 ml/min and after 50 mg indomethacin it was 126.5 ± 8.9 ml/min (P > 0.1). In 4 of the volunteers the mean creatinine clearance after 8 days on indomethacin 25 mg q.i.d. was 117.1 ± 5.3 ml/min (P > 0.1). Indomethacin plasma concentrations were in the usual range for the dose given. Indomethacin caused no reduction in the creatinine clearance in spite of...

The interaction between indomethacin and probenecid has been studied in 17 patients with rheumatoid arthritis with the use of a specific gas-liquid chromatographic method for the assay of indomethacin in plasma and urine. Probenecid in a dose of 0.5 gm twice daily improved the therapeutic response to indomethacin administered in a dose of 25 mg 3 times daily for a 3-wk period. There was an increase in the mean AUC of indomethacin in plasma from 2,553 +/- 213 hr ng/ml to 4,181 +/- 384 hr ng/ml when probenecid was given, but there was no change in the plasma half-life of indomethacin. There was a reduction in the mean plasma clearance of indomethacin from 174 +/- 21 ml/kg/hr to 107 +/- 14 ml/kg/hr when probenecid was added to the indomethacin therapy and a decrease in the apparent volume of distribution from 0,927 +/- 0.16 L/kg to 0.613 +/- 0.13 L/kg. There was no change in the amount of free indomethacin excreted in the urine during probenecid therapy but there was a reduction in the urinary excretion of free plus glucuronide conjugate of indomethacin from 8,967 +/- 867 microgram/day to 4,760 +/- 674 microgram/day, with a fall in the mean renal clearance of indomethacin glucuronide from 271 +/- 48 ml/min to 126 +/- 57.0 ml/min. The changes in the plasma indomethacin concentration profile during probenecid therapy are due to a decrease in the nonrenal clearance of indomethacin possibly because of reduced biliary clearance.

A sensitive and specific gas chromatographic method for the analysis of indomethacin has been developed. After extraction of the drug from blood or urine with ethylene dichloride a derivative is formed with pentafluorobenzyl bromide. 5-Fluoro-indomethacin is used as an internal standard. The overall recovery of indomethacin is 85.1 ± 2.3% and the method can detect 10 ng indomethacin in a 1 ml plasma or urine sample. No interference in the method is seen with some commonly used drugs. The method has been used to measure plasma indomethacin concentrations in 20 patients with rheumatoid arthritis, being treated with 25 mg indomethacin three times daily. The plasma concentration ranged from 168–596 ng/ml.

In a double-blind crossover study, it has been shown that the hypotensive response to propranolol in 24 patients with essential hypertension was no greater at doses of 80, 160, or 240 mg twice daily than at 40 mg twice daily. A relationship was observed between dose and response as defined by the ability to achieve a standing diastolic blood pressure of 95 mm Hg. Four patients with low plasma renin activity (PRA) had no fall in blood pressure even at highest dose levels. Plasma propranolol levels in the groups were related to dose, and up to a concentration of 300 ng/ml, with degree of beta-adrenoceptor blockade; there was, however, no correlation with hypotensive response.

Warfarin was measured with a sensitive and specific method in the plasma and breast milk of 13 mothers. Less than 0-08 micronmol warfarin per litre (25 ng/ml) of breast milk was found in each instance. Seven of the mothers were breast-feeding their infants, in none of whom was warfarin detected in the plasma; furthermore, in three the British corrected ratio of the plasma was appreciably less than that of the mother and was within the expected range. We conclude that nursing mothers given warfarin may safely breast-feed their infants.

It is now accepted that some patients will fail to respond clinically to one non-steroidal anti-inflammatory drug but will respond to another apparently similar compound (8). There are a number of possible reasons for this failure to respond such as the use of inadequate dosage or inappropriate drugs. However these reasons are unlikely to be applicable in the situation outlined above and we have been interested in exploring further, possible reasons for this failure to respond. We have therefore conducted two studies in patients with rheumatoid arthritis to examine the relationship between the pharmacokinetics of the drugs used, the clinical response to the drug, and certain biochemical effects of the drugs. The initial study with indometha-cin was reported more fully in 1979 (3) and the second study was reported more briefly in 1980 (II). This report reviews the initial study and reports on some new data in the second study.