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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.
In a metabolic ward study of five patients, azapropazone lowered plasma uric acid but exerted only a modest and variable uricosuric effect without altering urinary xanthine and hypoxanthine levels. An alternative mechanism other than uricosuria or xanthine oxidase inhibition must account for some of the hypouricaemic action of this drug. During the first day of treatment urine volume and pH declined sharply. In a separate investigation, 22 patients were given azapropazone and 18 were given allopurinol combined with colchicine for 3 months. Allopurinol reduced plasma uric acid more quickly but at the end of the study there was little difference in the hypouricaemic results achieved by both drugs. Recurrent gout occurred more frequently with allopurinol but side-effects were confined to those taking azapropazone. A slight rise in blood urea and creatinine and a fall in haemoglobin were also features of long-term azapropazone treatment.
The analgesic effect of 10 anti-inflammatory drugs was compared using a single-blind method in 90 patients with rheumatoid arthritis. Each patient received two different drugs, for three days each and each drug was evaluated in 18 patients. After the trial, the patients considered which of the drugs they preferred. The greatest relief from pain was achieved by diclofenac, indomethacin, naproxen and tolfenamic acid, each of these being preferred by the majority of patients and being significantly (p less than 0.01) better than the least effective drugs ketoprofen and proquazone. Acetylsalicylic acid, azapropazone, carprofen and ibuprofen were considered intermediate in efficacy.
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.
Activated neutrophils and possibly xanthine oxidase-derived free radicals are believed to be mediators of ischemia and reperfusion-induced myocardial damage. We studied the cardioprotective effect of the neutrophil stabilizer and xanthine oxidase inhibitor azapropazone in dogs subjected to thrombotic occlusion of the left anterior descending coronary artery (LAD), induced by intracoronary introduction of a copper coil, followed 60 min later by thrombolytic treatment with intracoronary streptokinase and 4-day reperfusion; we then determined infarct size by triphenyltetrazolium stain. Azapropazone [100 mg/kg intravenously (i.v.) followed by a 24-h i.v. infusion of 10 mg/kg/h, n = 8] or vehicle (n = 10) treatments were started immediately before the streptokinase infusion. Steady-state plasma levels of azapropazone ranged from 97 to 163 micrograms/ml during the infusion. Myocardial blood flow and underperfused area at risk were determined using radiolabeled microspheres. Results were as follows (mean +/- SEM): area at risk (percentage of left ventricle) azapropazone 22.7 +/- 3.16 and vehicle 21.8 +/- 4.13; infarct size (percentage of area at risk), azapropazone 45.1 +/- 11.8 and vehicle 75.7 +/- 10.6, p less than 0.03; collateral blood flow (ml/min/g), azapropazone 0.27 +/- 0.02 and vehicle 0.23 +/- 0.02; total ischemic period (min), azapropazone 106 +/- 5.9 and vehicle 91.5 +/- 4.9. Azapropazone had no effects on heart rate (HR), blood pressure (BP), or rate/pressure product (RPP). These dta show that azapropazone limits infarct size in a canine model of coronary thrombosis and long-term reperfusion and that this cardioprotection is independent of cardiovascular parameters.
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.
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.
1 The free fraction of azapropazone in the plasma of 37 healthy volunteers ranged from 0.0027 to 0.0070 (0.0044 +/- 0.0009, mean +/- s.d.). The principal binding protein was found to be albumin. 2 In 27 patients with various degrees of renal failure the free fraction values of azapropazone were markedly enhanced (0.0260 +/- 0.0239, mean +/- s.d.) and increased more than tenfold in some patients. There was a weak correlation (r = 0.46, P less than 0.05) between the free fraction and the clearance of endogenous creatinine. Such correlation was not found for serum creatinine, serum albumin, serum uric acid and serum urea nitrogen. 3 In 32 patients with chronic liver disease the free fraction values of azapropazone were also markedly higher (0.0210 +/- 0.0242, mean +/- s.d.) than in healthy subjects. There were statistical significant correlation between free fraction values and the prothrombin complex activity in the plasma (r = 0.40, P less than 0.05) and the total bilirubin concentration in the plasma (r = 0.90, P less than 0.001), respectively. Such correlation was not found for serum albumin, serum glutamic oxalacetic transaminase, serum gamma-glutamyl transpeptidase and serum alkaline phosphatase. 4 In patients with kidney and liver disease the free fraction values of azapropazone correlated well with those of the anticoagulant drug phenprocoumon (r = 0.93, P less than 0.001). However, the binding of the latter drug was less impaired. Bilirubin, when added in vitro, displaced both drugs from plasma proteins but this displacing effect was much smaller than the binding changes observed in patients with liver disease. 5 Kidney and liver disease caused a marked impairment of the plasma protein binding of azapropazone. In patients with kidney disease the degree of impairment of azapropazone binding cannot or only poorly (creatinine clearance) be predicted from the biochemical parameters of kidney function whereas in patients with chronic liver disease the total bilirubin concentration in the plasma may serve as an index of the binding defect.
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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.
We have investigated the interaction of azapropazone with phenytoin in five healthy volunteers. From steady-state plasma phenytoin concentrations of about 17 mumol/l there was at least a two-fold increase following the introduction of azapropazone. The main mechanism of the interaction was a decrease in phenytoin clearance, attributable to competitive inhibition by azapropazone of phenytoin p-hydroxylation. Protein-binding of phenytoin in the plasma (as assessed by salivary phenytoin concentrations) was significantly reduced from 92 to 90% by azapropazone and similar changes occurred in in vitro studies of [3H]-phenytoin protein binding.
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)
Ten healthy individuals received frusemide 40 mg orally for 7 days. Following a drug free period of 7 days they received azapropazone 600 mg twice daily for 7 days and then both treatments for a further 7 days. Sodium excretion fell from 141 +/- 16.8 mmol/day to 84.3 +/- 6.8 mmol/day (P less than 0.01) on initiation of azapropazone treatment. The natriuretic response to frusemide was unchanged by premedication with azapropazone. Urate excretion rose from 3.35 +/- 0.249 mmol/day to 4.98 +/- 0.365 mmol/day on initiation of azapropazone therapy but subsequently returned to baseline values. Plasma uric acid fell from 0.289 +/- 0.024 mmol/l to 0.167 +/- 0.0125 mmol/l (P less than 0.001) on azapropazone but rose to 0.186 +/- 0.0116 mmol/l (P less than 0.001) with the addition of frusemide. Azapropazone may cause sodium retention but after repeated administration frusemide still has a marked diuretic action. The hypouricaemic effect of azapropazone is only slightly antagonised by frusemide at the doses studied.
The biosynthesis of thromboxane (TX) B2 and immunoreactive prostaglandin (PG) F2 alpha in clotting whole blood ex vivo as well as collagen-induced platelet aggregation were determined before and up to 72 h after intravenous injection of 600 mg azapropazone 2H2O and intramuscular injection of 30 mg ketorolac tromethamine in six healthy subjects. The drug doses were selected on the basis of comparable analgesic activity (maximal recommended analgesic dose). Both platelet aggregation and prostanoid biosynthesis were inhibited by racketorolac to a significantly greater extent and for a longer period of time than by azapropazone. Correlations between serum concentrations and the inhibitory effects on TXB2 biosynthesis were observed for both drugs. Using the sigmoidal Emax model the mean serum concentration of azapropazone inhibiting platelet TXB2 generation by 50% (EC50) was found to be 98.1 +/- 41.9 (s.d.) micrograms ml-1, a value 1000 times higher than that for rac-ketorolac. The moderate inhibition of platelet function by azapropazone as compared with rac-ketorolac might be an advantage with regard to its use as a post-operative analgesic.
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.
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.
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.
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.