Effects of azapropazone on pain-related brain activity in human subjects.

1. The dose-related effects of azapropazone on (i) event-related and spontaneous EEG-activity and (ii) the subjects' pain ratings were investigated using an experimental human pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjects' pain ratings. 2. Healthy subjects (n = 20) participated in a placebo-controlled, randomized, double-blind, four-way cross-over study. Single doses of azapropazone (300 mg, 600 mg and 1200 mg) and placebo were administered intravenously. Each experiment consisted of five sessions (before and 1, 2, 4 and 8 h after administration of the medication). Each session lasted for approximately 40 min. In the first 20 min, pain was induced by short CO2-stimuli presented to the right nostril (phasic pain; interstimulus interval 30 s) and EEG was recorded from five positions. CSSERPs were obtained in response to painful CO2-stimuli. In the following 20 min period, tonic pain was induced by a constant stream of dry air introduced in the left nostril. Subjects rated the intensity of both phasic and tonic pain by means of a visual analogue scale. Additionally, a frequency analysis of the spontaneous EEG was performed. 3. Azapropazone reduced the pain-related CSSERP-amplitudes at frontal and parietal recording positions. This topographical pattern was observed in previous studies with opioids, while NSAIDs such as flurbiprofen and ketoprofen exerted effects at frontal and central positions. In contrast to other NSAIDs, administration of azapropazone resulted in a reduction of the frequency bands alpha 1, delta and theta of the spontaneous EEG. At the subjective level, analgesic effects of azapropazone were observed in the ratings of tonic pain. 4. Analgesic properties of azapropazone were demonstrated in man. The topographical pattern of the changes in the CSSERPs and the effects on EEG background activity suggest a central component of the analgesic action of azapropazone.

A new approach to encapsulating non-steroidal anti-inflammatory drugs. V. Biopharmaceutical study of microcapsules of azapropazone coated with pectin and rutin.

Azapropazone was encapsulated with pectin-rutin mixture using the fluidized bed technique. The encapsulated particles showed higher dissolution rate and bioavailability but lower ulcerogenic activity as compared with the drug alone.

Protection from gastrointestinal side-effects by azapropazone by its incorporation into a glucose-sodium acid citrate formulation.

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.

Myocardial cytoprotective efficacy of azapropazone in a canine heart model of regional ischemia and reperfusion.

The present study assessed the efficacy of azapropazone (AZA) in pentobarbital-anesthetized dogs subjected to 120 min of regional ischemia [left anterior descending coronary artery (LAD) ligation] followed by 5 h of reperfusion. Azapropazone was given 30 min prior to LAD occlusion (100 mg/kg i.v.), 35 min prior to LAD release (50 mg/kg, i.v.), and at 2.5 h postreperfusion (50 mg/kg i.v.). Regional myocardial blood flow (RMBF) and area at risk (AAR) were determined with radiolabeled microspheres. The degree and extent of ischemia (anaerobic metabolism) and necrosis were delineated with 14C-deoxy-2-D-glucose (14C-DG) and 111In-antimyosin, respectively, in control (n = 7) and AZA (n = 7)-treated groups. In mild (60-80% normal RMBF) and moderate (30-60% normal RMBF) flow-restricted areas, AZA resulted in a significant decrease in the degree and extent of ischemia (p less than 0.01) with the limitation of infarct size (p less than 0.01). However, AZA did not produce a significant infarct size limitation in the severe flow-restricted area (0-30% of normal RMBF). The effect of AZA is expressed primarily in moderate flow-restricted myocardium with the subsequent infarct size limitation.

[Human pharmacokinetics of different i.v. doses of azapropazone (HPLC-determination) (author's transl)]. / Humanpharmakokinetik verschiedener i.v. Dosen von Azapropazon (HPLC-Bestimmung).

The pharmacokinetic profile of azapropazone (Prolixan), sodium salt of 5-dimethylamino-9,5-dimethylamine-9-methyl-5-propyl-1H-pyrazolol[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione, was established. Six healthy, adult volunteers received a single dose of either 600 mg or 1200 mg azapropazone as sodium salt intravenously. The drug was selectively separated from its metabolites and other plasmatic compounds and it was quantified by measurement of extinction at 254 nm. The kinetic parameters of azapropazone were independent of the applied dose (600 mg and 1200 mg): Biological half-life (t0.5): 16.8 +/- 2.95 h and 17.2 +/- 3.0 h; Total clearance (Cltot): 10.2 +/- 2.1 ml min-1 (both doses); Central volume of distribution (Vc): 3.7 +/- 0.71 and 3.9 +/- 0.91; Apparent volume of distribution (Vd): 12.5 +/- 2.91 and 14.4 +/- 2.41. Initial serum concentrations were 170 +/- 41.5 micrograms ml-1 and 326.3 +/- 84.5 micrograms ml-1, determined by extrapolation (C0 at time t0). The areas under the plasma concentration curves (AUC0 infinity) were calculated to amount 1052.5 +/- 217.4 micrograms ml-1h-1 and 2078.4 +/- 515.9 micrograms ml-1h-1. Three rate constants associated with the elimination of the drug could be calculated.

Clinical therapeutic trial of aspirin and azapropazone in rheumatoid arthritis when prescribed singly and in combination.

A double-blind, crossover trial was carried out to assess the clinical efficacy of 3.6 g aspirin, 1200 mg azapropazone and the two drugs together in 24 adult patients with classical or definite rheumatoid disease. Pain score, morning stiffness and patients' assessment of pain were significantly improved for each drug regimen when compared to placebo. There was no significant difference among the individual drug regimens. Azapropazone was the best drug regimen in terms of improving pain score, morning stiffness and patient assessment of pain, but this was not statistically significant. It is concluded that there is no justification for prescribing aspirin with azapropazone in patients with rheumatoid disease.

Pharmacokinetics of azapropazone following single oral and intravenous doses.

The pharmacokinetics of azapropazone (Prolixan) was studied in 7 healthy volunters following single oral and i.v. doses of 600 mg. After i.v. injection plasma concentration declined biexponentially with time. The half-life of the beta-phase was 13.6 +/- 2.6 h (mean +/- SD), the apparent volume of distribution 11.9 +/- 3.5 l, and the total clearance 10.1 +/- 2.1 ml . min-1. Following oral administration peak plasma concentrations occurred between 3 and 6 h and declined with a beta-phase half-life of 14.3 +/- 2.8 h. The binding of azapropazone to plasma proteins was high (ranging from 99.52 to 99.67% at a total plasma concentration of 75 micrograms/ml). The bioavailability of azapropazone when administered as capsules was 83 +/- 19%.

[On the determination of azapropazone from plasma by direct quantitative thin-layer chromatography (author's transl)]. / Uber die Bestimmung von Azapropazon aus Plasma durch direkte quantitative Dünnschichtchromatographie.

For the purpose of investigating drug interactions, a new selective method for determination of 5-dimethylamino-9-methyl-2-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dione-dihydrate (azapropazone, Prolixan 300) was developed. The method is based upon the direct quantitation of the drug by thin-layer chromatography using remission measurement. The method is well suited for routine analysis of numerous samples, because of its simplicity and rapidity. The standar deviation of the method is about +/-4% at therapeutic plasma concentrations.

Clinical assessment of azapropazone in rheumatoid arthritis.

Azapropazone was investigated in a 2-week double-blind clinical out-patient trial against placebo in 23 patients with definite rheumatoid arthritis. The drug was given at a dose of 1200 mg. per day before food. At this dose level the drug was shown to have an antirheumatic effect in terms of pain relief, articular tenderness and duration of morning stiffness.

An assessment of the therapeutic potential of azapropazone in rheumatoid arthritis.

A trial to compare the therapeutic potential of 1200 mg. azapropazone daily with 3.9 g. aspirin daily was carried out in 108 out-patients with rheumatoid arthritis over a 14-day period. Analysis of results from the 85 patients with completed assessment data (49 on azapropazone; 36 on aspirin) showed that azapropazone was better than aspirin from the point of view of pain relief, number of days patients were withdrawn prematurely from the trial, and patient satisfaction with treatment. The differences, however, were not statistically significant. The authors compare the results obtained in this trial with those obtained previously from trials with 13 other antirheumatic drugs using the same method.

Prolonged treatment with azapropazone.

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.

Long-term use of azapropazone in rheumatoid conditions.

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.