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Sixty-three consecutive Behçet's syndrome patients with an acute arthritis of up to 10 days duration were treated either with azapropazone (APZ) 300 mg t.i.d. or placebo for three weeks. Twenty-eight patients (14 males, 14 females: mean age 36.2 +/- 8.1 SD years) from the APZ group and 29 patients (18 males, 11 females; mean age 34.2 +/- 8.4 SD years) from the placebo group completed the trial. At the end of the trial the arthritis persisted in 53.5% (15/28) of the APZ patients and in 41.3% (12/29) of the placebo patients (chi 2 = 0.85; NS). Six patients (6/28; 21%) from the APZ group and 9 patients (9/29; 31%) from the placebo group developed new joint involvement (chi 2 = 0.7; NS). There was no difference in the duration of arthritis between the two groups (19.9 +/- 8.3 SD days in the APZ groups vs. 19.7 +/- 8.2 SD days in the placebo group; NS). The degree of joint swelling, the tender joint score and the visual analogue score for pain significantly improved in both groups, but there was no difference in any of these parameters between the groups except for a significant difference in the visual analogue score for less pain at the first week in the azapropazone group (t = 2.23; p < 0.05). There were also no differences in the mean numbers of acetaminophen tablets used or in the CRP and ESR levels between the two groups. We conclude that azapropazone is not effective in controlling the arthritis of Behçet's syndrome.

The relationship between endoscopically observed gastric mucosal damage, elicited following repeated oral intake for 7 d of four NSAIDs, to their effects on antral and fundic production of PGE2, 6-keto-PGF1 alpha and TxB2 (assayed by GC-MS), mucosal histology and plasma concentration profiles was studied in 40 normal males. Subjects received azapropazone (APZ) 600 mg b.i.d., indomethacin (IND) 50 mg t.i.d., naproxen (NAP) 500 mg b.i.d., piroxicam (PIR) 20 mg qq.d., or one placebo capsule t.i.d. (N = 8/group). Plasma NSAIDs (HPLC) levelled at 7 d. Mucosal damage occurred in the antrum region with IND and NAP. APZ and PIR exhibited no differences compared to placebo. NAP and IND reduced all three prostanoids in the antrum while APZ and PIR were ineffective. Fundic PGE2 was reduced by IND, NAP and PIR; APZ had no effects. Thus, mucosal damage relates to effects on prostanoid production in the antrum but not in the fundus.

The damage of the mucous membranes in the gastrointestinal tract caused by non-steroid antiinflammatory drugs are well known. The gastrointestinal microbleeding was measured by the method of Fischer and Hunt before and after the intake of indomethacin (4 x 25 mg), naproxen-sodium (4 x 275 mg), diclofenac (3 x 50 mg) and azapropazone (2 x 600 mg). In the indomethacin group microbleeding increased from 0.91 +/- 0.12 ml/24 h to 7.30 +/- 1.20 ml/h. In the naproxen-sodium group from 1.22 +/- 0.16 ml/24 h to 3.56 +/- 0.40 ml/24 h, in the diclofenac group from 0.86 +/- 0.14 ml/24 h to 3.18 +/- 0.28 ml/24 h, in azapropazone group from 0.92 +/- 0.18 ml/24 h to 2.50 +/- 0.20 ml/24 h, respectively. All non-steroid antiinflammatory drugs increased the gastric microbleeding, however, there were considerable differences in the degree of enhancement. This can be explained by the different inhibitory activities of the drugs on the cyclooxygenase enzyme activity.

Eighty patients received one of three treatments after elective dental surgery involving multiple extractions. Group A received aspirin 600 mg, group B azapropazone 300 mg and group C azapropazone 600 mg. All drugs were administered in a double-blind fashion. Quality of analgesia was unsatisfactory for all treatments; over 30% of patients required supplementary analgesia with an opioid. In addition there were a large number of withdrawals from the study. There were no significant differences in analgesic efficacy between groups.

Addition of glucose and sodium citrate to azapropazone, in proportions of 1:1:1 by weight reduced gastric mucosal damage in rats and there was a trend towards reduction in radiolabelled faecal red cell loss in human volunteers compared with that with azapropazone alone. The glucose and citrate did not affect the pharmacokinetics of azapropazone, or its therapeutic efficacy. While no difference was observed in endoscopic injury and in symptomatic gastrointestinal complaints in a multicentre comparison in rheumatic patients, a striking reduction in symptoms was observed in those patients with a history of severe gastrointestinal intolerance to non-steroidal anti-inflammatory drugs.

2 patients on the drug azapropazone developed positive antiglobulin tests. Their sera were each found to contain two distinct antibodies. One was an IgG antibody, probably a drug-dependent autoantibody of the alpha-methyldopa type, but could have been related to the disease. The other was certainly a drug-dependent antibody of the penicillin type.

We report an episode of bone marrow hypoplasia following the administration of azapropazone to a patient stabilized on regular methotrexate for psoriasis. A pharmacokinetic interaction is postulated.

Azapropazone is a new, powerful, antiinflammatory analgesic. Initial trails have confirmed its efficacy as an antirheumatic agent, with a low incidence of adverse reactions. Recently the authors have seen two patients, each of whom developed a distinctive but clinically dissimilar, bizarre, bullous eruption after taking this drug. A brief account of these cases has been published elsewhere (1).

A double-blind crossover study in 41 patients with knee joint osteoarthrosis was carried out to compare the efficacy of 1200 mg. azapropazone per day with 1600 mg. ibuprofen per day. After an initial week on placebo, patients received one or other of the active medications for 2 weeks, then a 1-week placebo wash-out period before being crossed over to the alternative drug for a further 2 weeks. Objective assessments were made of knee joint movement, and of knee joint and thigh circumference. Patients made daily assessments of pain and a final overall assessment of preference for one or other treatment period. The results showed that azapropazone produced a significant improvement (p less than 0.05) in knee joint mobility over placebo, both active drugs were more effective than placebo (p less than 0.05) in providing pain relief, but that there was no significant difference between the two in these parameters. There was a highly significant patient preference, however, for azapropazone (p less than 0.01) compared to ibuprofen treatment periods. The most commonly reported side-effect with both drugs was dyspepsia, but in no case was it sufficiently severe to necessitate stopping treatment.

A double-blind crossover trial in 50 patients with rheumatoid arthritis was carried out to compare the clinical effectiveness of 800 mg. azapropazone per day with 100 mg. indomethacin per day. Blood plasma concentrations of azapropazone were also studied in 10 patients. Patients received both drugs for a 3-week period, the order of treatment being determined at random. Although there were no marked differences in any of the objective measurements, patients assessments of response to and preference for each drug treatment period suggested that azapropazone produced significant improvement compared to that with indomethacin. Plasma levels of azapropazone remained remarkably constant for each patient. Side-effects with both drugs were mild and transient, and there were no marked variations from normal in any of the laboratory parameters measured.

A double-blind crossover study to compare 1200 mg. azapropazone per day with 100 mg. indomethacin per day was carried out on 34 patients with psoriatic arthritis and 16 patients with Reiter's disease. The same comparison was initiated in 8 additional patients but withdrawn in 3 cases because of side-effects to indomethacin, in 2 cases because of side-effects to azapropazone, and in the 3 remaining cases for other stated reasons. The results of the study showed no overall difference between the treatment results of azapropazone and indomethacin, but azapropazone seemed to be more effective in cases with psoriatic arthritis and indomethacin in cases with Reiter's disease. Indomethacin caused more side-effects than azapropazone. Neither drug seemed to influence the skin manifestations of either disease.

A long-term open assessment of azapropazone (900 mg to 1200 mg daily) was carried out in 51 patients suffering from osteoarthritis for periods of up to 1 year. Of these patients, 70% completed 9 to 12 months of treatment. Clinical assessments were made before and during the study of pain on motion or weight bearing, night pain, functional activity, morning stiffness, doctor's overall assessment, patients' overall assessment, and details of side-effects recorded. There were statistically significant improvements in the mean rating scores for each of the clinical assessments and these became apparent at 1 month, maximal at 3 to 6 months and persisted at the same level to the end of the trial. There were no side-effects recorded at any period of the trial in 30 (59%) patients. When side-effects did occur they were mild in 12 (24%), moderate in 3 (6%) and severe in 6 (12%) patients. The most frequent side-effects were related to the gastro-intestinal tract and gastric pain occurred in 7 (14%) patients, whilst rash or eczema occurred in 4 (8%) patients. It was concluded that, for the patients in the trial, long-term treatment with azapropazone was a useful and effective procedure.

An impairment of the renal function was observed in three patients who received azapropazone for various rheumatic disorders with simultaneous hyperuricaemia. A distinct increase in serum creatinine occurred in all patients. In one case the renal biopsy suggested a hypersensitivity reaction with a consequent acute tubulo-interstitial nephritis as the mechanism of the impaired renal function. The renal insufficiency was reversible in all cases after the withdrawal of azapropazone.

A comparative study was carried out, using the Cr51 red blood cell labelling method, to assess the amount of gastro-intestinal blood loss in 20 rheumatoid arthritis patients taking either 600 mg. or 1200 mg. azapropazone daily. The results demonstrate that azapropazone does not produce greater than normal gastro-intestinal bleeding, that the volume of faecal blood loss is not dose-related, and there would not appear to be any correlation between blood loss and the occasional mild gastro-intestinal side-effects reported in a few patients. These results compared favourably with those obtained previously by the investigators in a similar group of patients taking 3 g. aspirin per day.

The gastro-intestinal tolerance of azapropazone, a new non-steroidal anti-inflammatory agent, was studied endoscopically in 14 volunteers with no past history of gastro-intestinal disease. This study shows that gastrointestinal tolerance to azapropazone given in a daily dose of 1200 mg for a period of 31 days is good. Istolated erosions with mild hyperemia were found in 2 subjects only. No subjective symptoms were noted during the period of the study.

In an open assessment of azapropazone, 51 patients with rheumatoid disorders, mainly rheumatoid arthritis, were treated continuously for periods up to 3 years (range 2 weeks to 38 months). Treatment was interrupted or discontinued in 9 patients for various reasons. Initial dosage was 1200 mg. daily, but this was usually reduced after a few months to a maintenance level of 900 mg. daily. An overall assessment of patient response at the end of the study period indicated that only 4 (7.8%) of the 51 patients failed to obtain satisfactory relief during treatment: 28 (54.6%) showed objective signs of improvement, such as reduced joint swelling and stiffness, as well as subjective evidence of symptom relief, and a further 19 patients (37.3%) reported an equivocal analgesic effect with azapropazone. Few side-effects were reported, mainly mild gastralgia and nausea, and routine laboratory investigations throughout the long-term study revealed no abnormalities in the blood picture, liver or renal function or coagulation factors. There was also no evidence of any interaction between azapropazone and other drugs used concomitantly.

To test the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) accelerate the progression of osteoarthritis by reducing synthesis of vasodilator prostaglandins, thereby diminishing joint perfusion, 105 osteoarthritis patients awaiting hip arthroplasty were treated prospectively with a strong or weak prostaglandin synthesis inhibitor, indomethacin or azapropazone, respectively. Pain and radiological joint space were monitored during the period up to arthroplasty and the condition of the excised femoral head was determined. As judged by radiological and histopathological data, the two treatment groups were at a similar pathophysiological end-point when they came to arthroplasty. In the indomethacin group the affected hips lost joint space more rapidly than did the contralateral hips, a difference not seen in the azapropazone group. The patients receiving azapropazone, who had higher concentrations of synovial vasodilator prostaglandins, took longer than the indomethacin group to reach the arthroplasty end-point. Potent inhibitors of prostaglandin synthesis may be inappropriate in the management of osteoarthritis of the hip.

Eight patients with acute gouty arthritis were treated with high dose oral azapropazone 600 mg qds in an open study in order to evaluate its therapeutic potential in acute gout. The drug appeared to be as effective as previous agents used in the management of individual patient's acute gout with resolution of pain in 2-21 days, and it had a potent hypouricaemic and uricosuric effect. The uricosuric effect of azapropazone 300 mg qds and phenylbutazone 100 mg tds was compared in a seven day cross-over study in seven asymptomatic patients with gout and hyperuricaemia. Azapropazone had a more rapid uricosuric effect than phenylbutazone. There was a statistically significant fall in serum uric acid and rise in uric acid clearance 24 hours after starting azapropazone and 72 hours following phenylbutazone.

In 3 years seventeen patients presented to one unit with renal failure associated with the use of non-steroidal anti-inflammatory drugs (NSAID). Seven patients presented with acute renal failure, in four due to acute tubular necrosis and in three to acute interstitial nephritis; all recovered when NSAID treatment was stopped. Four patients presented with symptomless renal impairment discovered during routine follow-up in a rheumatology clinic; again all improved on withdrawal of NSAID. The remaining six patients presented with chronic renal failure, a disorder not previously associated with NSAID treatment. The pattern of renal disease associated with NSAID may be more extensive than has previously been recognised. A history of NSAID use should be sought in all patients presenting with unexplained renal failure.

We report a case of hypoglycaemia due to a 'first-dose' interaction between azapropazone and tolbutamide. The mechanism was probably by displacement of tolbutamide from protein binding sites, and it is recommended that azapropazone should be avoided in patients receiving tolbutamide.

A double-blind trial of azapropazone (300 mg. 4-times daily) and ketoprofen (50 mg. 4-times daily) was carried out in 50 patients with acute backache sufficiently severe to necessitate hospital admission. Of 39 patients who completed the full 3-weeks' study period, 18 preferred azapropazone therapy, 10 preferred ketoprofen, and 11 showed either preference for the intermediate placebo period or no preference at all. Ten patients suffered from sufficiently severe side-effects with ketoprofen to necessitate their withdrawal from the trial. There were no similar episodes of withdrawal occurring during the azapropazone period.

In an open study of 40 patients with chronic rheumatoid polyarthritis, azapropazone was given alone in daily doses between 1200 mg. and 1800 mg. over a period of 6 months. Six patients were withdrawn, 2 because of side-effects (1 with an allergic-type rash; 1 with ankle oedema) and 4 because azapropazone alone did not provide adequate control of their pain and discomfort. Objective assessments showed that 18 patients had a 'good' or 'very good' response to treatment, and a further 16 showed moderate improvement. These findings were supported by the patients' subjective assessment of the change in their condition from the start of the trial. In addition, 22 patients showed a significant decrease in erythrocyte sedimentation rate. There was no evidence of adverse effects on any of the haematological and biochemical parameters measured, and the incidence of side-effects was low.

Letters in correspondence columns or brief reports in medical journals are an essential part of an early warning system, and they are invaluable in alerting clinicians and clinical pharmacists to associations between drugs and their reactions. A survey of the literature during the first half of 1982 has identified a number of these early reports; some are purely anecdotal, others may be coincidental, but all serve to warn the practitioner of potential hazard. Brief information on the following reports of drug-drug interactions is given in this article with the intention of giving these reports wider publicity and, possibly, encouraging further observation and research to establish or disprove their validity in a larger and wider range of patients or volunteer subjects. The following interactions are reviewed: amiodarone-quinidine, lidocaine-prenylamine, erythromycin-carbamazepine, azapropazone-phenytoin, chlordiazepoxide-levodopa, gentamicin-furosemide, ethanol-aspirin, acetaminophen-coumarin anticoagulant, and cimetidine-lidocaine.

The authors review the trials carried out on azapropazone in rheumatoid arthritis and other rheumatoid conditions. They comment that in terms of efficacy azapropazone would appear to be a useful non-steroidal anti-inflammatory analgesic which compares favourably with other established antirheumatic agents against which it has been tested. Its main advantages are its low incidence of side-effects and the fact that in the majority of the trials reported azapropazone treatment was preferred by patients to that with other agents.