The effect of prostaglandin synthetase inhibitors on human preovulatory follicular fluid prostaglandin, thromboxane, and leukotriene concentrations.

This study evaluates the eicosanoid concentration in luteinized unruptured follicles (LUFs) on the ovaries of patients who had been treated with inhibitors of prostaglandin synthetase. Indomethacin, bromfenac, or azapropazone (or a placebo) was administered orally to 41 women during the periovulatory period. Follicular development was monitored by serial ultrasound examinations, and the onset of ovulation was regulated by an injection of hCG. Follicular fluid was aspirated during sterilization by minilaparotomy, which was performed just before the expected time of ovulation. Prostaglandin E2 and PGF2 alpha levels in the fluid were significantly reduced by indomethacin and bromfenac compared to those after placebo treatment. Bromfenac also reduced the follicular fluid leukotriene B4 level. Therefore, the development of luteinized unruptured follicles after treatment with nonsteroidal antiinflammatory drugs appears to be associated with a significant decrease in the synthesis of ovarian eicosanoids.

Evaluation of the effect of azapropazone on neutrophil migration in anaesthetized swine using a multichamber blister suction technique.

1. The purpose of this study was to determine the in vivo inhibitory efficacy of azapropazone on neutrophil migration. The effects of azapropazone given at a dose of 100 mg kg-1 i.v. every 2 h on the neutrophil migration into skin inflammation sites (blister fluid) as well as into an autologous serum (+/- chemoattractant) placed above the blister surface (2nd chamber) were determined. 2. Azapropazone treatment schedule maintained blood levels at 70-100 micrograms ml-1 throughout the time course (360 min) of the experiment. 3. Azapropazone significantly inhibited (48 +/- 6%) neutrophil migration into the blister fluid (as evident from the decrease in myeloperoxidase activity). 4. Azapropazone significantly inhibited the neutrophil migration into the autologous serum either with (65 +/- 5%) or (35 +/- 6%) without the chemoattractant, formyl-methionyl-leucyl-phenylalanine (FMLP). The chemoattractant, FMLP, markedly increased neutrophil migration into the autologous serum by approximately 1.5 to 2 times the non-FMLP treated group. Azapropazone was more efficacious in inhibiting the neutrophil migration in the presence of FMLP than in its absence. 5. We conclude that azapropazone is an effective inhibitor of neutrophil migration into topically inflamed sites in anaesthetized swine.

Evaluation of the effect of azapropazone on neutrophil migration in regional myocardial ischaemia/reperfusion injury in rabbits.

1. The purpose of the present study was to determine the myocardial cytoprotective efficacy of azapropazone (AZA) and its potential site of action on neutrophil infiltration into reperfused/ischaemic myocardium with or without in vivo activation of neutrophils in rabbits. 2. AZA, 100 mg kg-1, was administered i.v. 10 min after occlusion of the left circumflex (LCX) artery in rabbits with and without pretreatment with phorbol myristate acetate ester (PMA). The LCX occlusion was then released at 10 min after AZA administration. Haemodynamic parameters (heart rate, LV pressure, mean arterial blood pressure and dp/dt) were monitored throughout the experiment. After 60 min reperfusion, the area at risk was delineated and the heart was then excised and divided into epi- and endocardial pieces for analysis of myeloperoxidase activity. 3. AZA inhibited neutrophil infiltration into the reperfused/ischaemic rabbit myocardium with and without PMA treatment. The inhibition of neutrophil infiltration was more apparent in the epicardium than in the endocardium. Additionally, AZA inhibited to a similar extent the in vivo PMA-stimulated neutrophil migration into the epicardium and endocardium area at risk. AZA had no significant effect on the haemodynamic parameters as compared to control. 4. AZA administered in an anaesthetized rabbit model of LCX occlusion/reperfusion resulted in the reduction of infarct size. 5. It is concluded that AZA has significant inhibitory effects on neutrophil migration which might contribute to its myocardial cytoprotective effect.

Inhibition of rat neutrophil functional responses by azapropazone, an anti-gout drug.

Azapropazone at concentrations of 0.1 to 1 mM inhibited by 30-70% rat neutrophil migration, aggregation, and degranulation in response to the synthetic chemotactic peptide fMet-Leu-Phe. Binding studies using fNle-Leu-[3H]Phe, a radiolabeled analog of fMet-Leu-Phe, showed that azapropazone did not inhibit these responses by interfering with fMet-Leu-Phe binding. Azapropazone also decreased both the apparent rate of production and maximal levels of superoxide anion (O2-) generated by cells stimulated with 100 ng/ml phorbol-12-myristate-13-acetate (PMA). The concentrations of azapropazone that inhibit these neutrophil responses in vitro approximate those previously found in vivo after administration of therapeutic doses of drug to rats or humans. Taken together, the data suggest that the efficacy of azapropazone in gouty arthritis may be partly due to its ability to inhibit key neutrophil functional responses in vivo.

Effect of azapropazone and allopurinol on myocardial infarct size in rats.

The effect of the xanthine oxidase inhibitor allopurinol and the non-steroidal antiinflammatory agent azapropazone on infarct size in rats, subjected to 48 h of occlusion of the left anterior descending coronary artery, were studied. Allopurinol (50 mg/kg i.p., twice daily from 24 h before to 48 h after LAD occlusion) and azapropazone (100 mg/kg i.p twice daily from 24 h before to 48 h after LAD occlusion) significantly reduced infarct size when compared to saline-treated rats. These data point towards involvement of xanthine oxidase derived free radicals in evolving myocardial infarction in rats; beneficial effect of azapropazone in this model may be related to the drug's ability to inhibit xanthine oxidase as well as various key neutrophil functions.

The pharmacology and pharmacokinetics of azapropazone - a review.

The pharmacology and pharmacokinetic properties of azapropazone, a new anti-inflammatory analgesic, are reviewed. Anti-inflammatory activity was assessed by standard in vivo and in vitro methods. The drug was shown to have definite activity with a potency approximately half that of phenylbutazone. Azapropazone was absorbed from the gastro-intestinal tract in animals and man, although wide inter-species variation in pharmacokinetic properties was noted. In man, the biological half life was approximately 20 hours. Azapropazone is not extensively metabolised and most metabolites have been identified and assayed.

Photoproducts of benzydamine and azapropazone: demonstration of their phototoxicity in vitro.

Red blood cell lysis, photosensitized by the products of the aerobic photolysis of benzydamine (1) and azapropazone (4), was investigated. Irradiation of a methanol solution of 1 and 4 under oxygen produces the photoproducts 3-hydroxy-benzydamine, (2), 2-(3-dimethylaminopropyl)-1-benzylindazolin-3-one (3) and 3-dimethylamino-7-methyl-1,2,4-benzotriazine (5). The mechanism of the photodegradation of 1 was examined. Photoproducts 3 and 5 produce singlet oxygen as demonstrated by trapping with 2,5-dimethylfuran. The photohemolysis rate for the photoproducts 3 and 5 was enhanced by deuterium oxide and oxygen. No change was observed in the presence of reduced glutathione. The photohemolysis rate was low under anaerobic conditions.

Comparative effects of azapropazone on cellular events at inflamed sites. Influence on joint pathology in arthritic rats, leucocyte superoxide and eicosanoid production, platelet aggregation, synthesis of cartilage proteoglycans, synovial production and actions of interleukin-1 in cartilage resorption correlated with drug uptake into cartilage in-vitro.

Azapropazone (APZ) has been compared with standard NSAIDs in title systems to establish aspects of its mode of action on cellular events at inflamed sites. APZ (150 mg kg-1 day-1) given for 10-13 days exhibited a reduction in joint pathology in established adjuvant arthritis in rats comparable with that of indomethacin (2 mg kg-1 day-1) and clobuzarit (20 mg kg-1 day-1). APZ was shown to be a potent inhibitor of the production of leucocyte superoxide and synovial interleukin-1 (IL-1)-like activity and stimulated articular cartilage proteoglycan synthesis, but was ineffective as an inhibitor of platelet aggregation or IL-1 induced cartilage degradation in-vitro. These in-vitro effects may have relevance to the mode of action of this weak inhibitor of prostaglandin synthesis.

Lack of activity of azapropazone in the hot-plate test and in 5-HT1A and 5-HT2 receptor subtypes in rat brain membranes.

This study aimed to investigate the antinociceptive activity of azapropazone (AZA), a weak prostaglandin synthesis inhibitor using the hot-plate test, and its ability to modify the serotonin-binding capacity in rat brain membranes. It revealed that AZA had no antinociceptive effect in the hot-plate test at the doses of 400 and 600 mg/kg when orally administered (p.o.), and at 400, 500 and 600 mg/kg after intraperitoneal injection (i.p.). At the dose of 600 mg/kg i.p. the drug failed to modify the number and the affinity of 5-HT1A and 5-HT2 receptors in rat brain membranes. In accordance with our previous findings on a positive correlation between NSAIDs antinociception in this experimental model and changes in 5-HT receptor characteristics, these results suggest an association between the lack of AZA-mediated antinociception in the hot-plate test and the drug's inability to modify the characteristics of 5-HT1A and 5-HT2 receptor binding sites in rat brain membranes.

[In vitro investigations on the influence of various antirheumatic drugs on the enzymes of the purine salvage pathway (author's transl)]. / In-vitro-Untersuchungen über den Einfluss verschiedener Antirheumatika auf die Enzyme des Purin-Wiederverwertungsstoffwechsels

On testing the effect of 5 drugs (azapropazone, flufenamic acid, indomethacin, oxyphenbutazone and prednisolone) commonly used in the therapy of rheumatic diseases on 3 enzymes of the purine salvage pathway (adenine-phosphoribosyltransferase, guanine-phosphoribosyltransferase and hypoxanthine-phosphoribosyltransferase) a distinct inhibitory effect of oxyphenbutazone and flufenamic acid was noted. A particularly marked effect was observed on adenine-phosphoribosyltransferase at the applied concentration (50 mug%) by both drugs but also guanine-phosphoribosyltransferase and hypoxanthine-phosphoribosyltransferase indicated reduced activities.

Comparative effects of some non-steroidal anti-inflammatory drugs on the ultrastructural integrity and prostaglandin levels in the rat gastric mucosa: relationship to drug uptake.

Studies were performed in fasted rats to establish if the propensity of 4 non-steroidal anti-inflammatory (NSAI) drugs to elicit varying degrees of gastric mucosal damage following oral administration is related to their rate of absorption by the mucosal and subsequent inhibitory effects on prostaglandin (PG) production in vivo. Aspirin (200 mg/kg p.o.) and indomethacin (10 mg/kg p.o.) produced ultrastructural signs of damage at 10-60 min to the surface mucous cells, parietal cells and endothelial cells of sub-mucosal capillaries coincident with the relatively rapid absorption of the radiolabelled drugs and reduction in the mucosal content of PGE2 and 6-keto PGF1 alpha determined by gas chromatography/mass spectrometry. Azapropazone (100 mg/kg p.o.) failed to elicit mucosal damage either ultrastructurally or even visually up to 23 h after dosing and did not affect the content of PG's even though the drug was present in the mucosa in sufficient concentration to elicit reduction in prostaglandin synthesis in vitro. Benoxaprofen (110 mg/kg p.o.) reduced the content of PGE2 and somewhat variably, that of 6-keto PGF1 alpha, was more slowly absorbed c.f. aspirin and indomethacin, but failed to elicit appreciable mucosal damage. These results show that while reduction in PG synthesis is a factor in the development of damage by ulcerogenic drugs, it appears that the rate of absorption or other biochemical effects (including e.g. influences on the production of oxyradicals or 5-lipoxygenase products of eicosanoid metabolism) may contribute to the relatively low irritancy of drugs such as azapropazone or benoxaprofen.

The uricosuric action of azapropazone: dose-response and comparison with probenecid.

Azapropazone is an anti-inflammatory agent with reported uricosuric properties. The aim of the present study was to extend these observations, by examining the dose-response and to compare the uricosuric effect of azapropazone with that of probenecid. Patients were given varying doses of azapropazone from 900-2400 mg daily for 4-day periods at separated intervals. Plasma uric acid levels were measured before and at the end of each treatment period. Three other patients maintained on low purine diets were given a 4-day course of 1200 mg azapropazone daily followed at an interval by a 4-day period of probenecid 1 g daily. Plasma uric acid levels and 24 h urinary uric acid excretion were compared. The mean fall in plasma uric acid level after four days of 900 mg azapropazone daily was 31.4% (n = 9) compared with 33.9% (n = 12) on 1200 mg daily; 42.3% (n = 10) on 1800 mg daily; and 46% (n = 6) on 2400 mg daily, indicating a graded dosage response. In the three patients on low purine diets the falls in plasma uric acid levels on probenecid 1 g daily were 50.5%, 46% and 29% compared with 33.5%, 32% and 20% respectively on azapropazone 1200 mg daily. Similarly the total amount of uric acid excreted in the urine by each patient during the 4-day period on probenecid 1 g daily was 14.01; 13.03 and 8.97 mmol compared with 23.53, 10.9 and 7.69 mmol on azapropazone 1200 mg daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of azapropazone in the elderly.

Plasma concentrations of azapropazone have been measured in young and elderly subjects after a single dose of 600 mg azapropazone. Maximum concentrations were higher in the elderly. Renal function was impaired in the older subjects. Mean azapropazone clearance was significantly reduced (P less than 0.001) in the old, compared to the young. Elimination half-life was prolonged but the difference did not reach statistical significance due to the wide variation of the values in the elderly. The volume of distribution of azapropazone and degree of adipose tissue did not differ between the two groups. Azapropazone clearance correlated well with creatinine clearance (P less than 0.001) when all the subjects were included and for the younger subjects only but not for the elderly patients alone. The addition of fat mass into the regression equation improved the relationship in all groups but in the older group levels of statistical significance were not achieved. Reasons for the difference between young and old are discussed. The effects of age on the pharmacokinetics of azapropazone suggest that therapeutic plasma levels may be achieved with a dose of 600 mg daily.

In vitro inhibition of xanthine oxidase by azapropazone and 8-hydroxy-azapropazone.

It has been demonstrated that the nonsteroidal antiinflammatory agent azapropazone (Prolixan) as well as its principal 8-hydroxy-metabolite have distinct xanthine oxidase inhibitory activity. The pharmacological spectrum of this compound has thus shown an interesting extension.