Effects of pirazolac on arachidonic acid metabolism in the human synovial system.

Six patients suffering from rheumatoid arthritis with massive knee joint effusions were treated with single daily doses of 600 mg pirazolac, a novel non-steroidal anti-inflammatory drug, for 3 days. Before the first dose, 3 hours after the second and the third dose, specimens of plasma and synovial fluid were drawn simultaneously. Plasma and synovial fluid concentrations of pirazolac, as determined by HPLC, amounted to 47.9 micrograms/ml and 19.8 micrograms/ml (Day 2) and 55.5 micrograms/ml and 18.7 micrograms/ml (Day 3), respectively. The samples were analyzed for PGE2, LTB4, LTC4 and LTD4 applying various extraction procedures and subsequent radioimmunoassays. PGE2 levels decreased during treatment from 928 pg/ml to 443 pg/ml after the third dose of pirazolac. LTB4 levels were slightly but insignificantly augmented. LTC4 and LTD4 concentrations were below the detection limit prior to and after administration of the drug.

Transsynovial distribution and protein binding of pirazolac in patients with rheumatoid arthritis.

Following a washout period of 7 days, twenty-one patients suffering from rheumatoid arthritis and 3 from osteo-arthritis, who all required articular puncture were given a non-steroidal anti-inflammatory drug pirazolac 450 mg b.d. for 7 days. After discontinuation of the treatment the subjects were divided into 4 groups each of 6 patients. The non protein bound fraction of pirazolac in synovial fluid (0.86%) was significantly higher than that in plasma (0.53%). The average pirazolac concentration in plasma within the dosing interval fluctuated between 30.9 micrograms/ml and 59 micrograms/ml, and in synovial fluid between 16.6 micrograms/ml and 29.9 micrograms/ml. The half-life of pirazolac calculated from the measured and interpolated data from all patients was 30.9 h in plasma and 66.2 h in synovial fluid. The absolute free concentrations in plasma and synovial fluid (approx. 250 ng/ml) were in the range of the IC50-values for inhibition of cyclooxygenase in mouse peritoneal macrophages.

Differential dosing study of pirazolac, a new non-steroidal anti-inflammatory agent, in patients with rheumatoid arthritis.

Twenty-four patients with classical or definite rheumatoid arthritis participated in a 4-week double-blind crossover study to compare the effectiveness of two different dosage regimens of pirazolac. Patients were allocated at random to receive 2-weeks' treatment with either 300 mg pirazolac in the morning and 600 mg at night or 450 mg pirazolac given morning and evening, and were then crossed over to the alternative regimen for a further 2 weeks. Physician assessments of disease activity were carried out on entry and at the end of each treatment period, and patients kept a daily record of visual analogue scale scores for pain and stiffness. The results showed that both dosage regimens of pirazolac produced a significant improvement in the parameters assessed, but the difference between the two regimens was not significant. However, overall assessment at the end of the trial by the 23 patients who completed the study showed that 14 preferred the 300/600 mg regimen compared with 7 who preferred the 450/450 mg regimen: 2 patients considered both regimens equally effective. Pirazolac was relatively well tolerated, only a few patients reporting gastro-intestinal (2) and skin (3) side-effects during the trial period.

Comparison of occult blood loss caused by pirazolac and diclofenac sodium: a double-blind crossover study.

A study was carried out in 10 healthy subjects to compare the faecal blood loss caused by pirazolac, a new non-steroidal anti-inflammatory drug, and diclofenac sodium, using chromium51-labelled red blood cells. After 1 week on placebo, subjects received at random either 200 mg pirazolac 3-times daily or 50 mg diclofenac sodium 3-times daily for 7 days. They were then crossed over to the alternative medication for a further 7 days, preceded and followed by 1 week on placebo. Stool samples were collected and bulked for each day and total blood loss over 14 days (7 days on treatment and 7 days immediately after) was calculated for each period. The results showed that both drugs caused a greater blood loss than that measured in the placebo run-in period, and diclofenac sodium caused significantly greater blood loss than did pirazolac. Three subjects reported gastro-intestinal side-effects during diclofenac sodium treatment but there were no reports of any side-effects whilst subjects were receiving pirazolac.

Circadian variation in disease activity in rheumatoid arthritis.

Disease activity in rheumatoid arthritis as measured by repeated estimation of joint pain, stiffness, articular index, and grip strength was shown to have a circadian rythm, maximal activity being seen between 0200 and 0400 and minimal activity in the early afternoon. This variation in disease activity may be related to circadian alterations in immune and inflammatory responses (such as immune complexes and neutrophil function) dependent on alterations in circulating concentrations of steroids. The circadian variation in disease activity has important implications in assessment of patients, prescription of drugs, and performance of drug trials.