Repeated cyclosporine therapy of peripheral arthritis associated with ankylosing spondylitis.

BACKGROUND: A case history of a patient with ankylosing spondylitis and peripheral arthritis unresponsive to the conventional drug therapy, but successfully controlled by the use of cyclosporin. MATERIAL AND METHODS: In a 68 years old female patient with a 36 years history of typical ankylosing spondylitis a peripheral polyarthritis (hands, feet, wrists, and knees) developed. The patient did not suffer any other disease known to cause secondary spondylitis (psoriasis, inflammatory, bowel, disease). After the unsuccessful use of non-steroidal antiinflammatory drugs a combination therapy with cyclosporin (4 mg/kg/day) and azapropazone (300 mg t.i.d.) was introduced. RESULTS: Clinical improvement was achieved after 6 months of combined therapy, the polyarthritis completely resolved after one year. Therefore cyclosporin was discontinued. After one year the polyarthritis reappeared therefore the cyclosporin therapy was reinstituted with success. CONCLUSION: Cyclosporin has proved consistently effective in our case to control the peripheral arthritis associated with ankylosing spondylitis.

Pharmacotherapy for Behcet's syndrome.

OBJECTIVES: To determine the effects of available pharmacological interventions in treating the different clinical features of Behcet's syndrome. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register, and Medline up to January 1998. The computer search was complemented by a hand search of all bibliographic references from the reference lists of included trials. Principal investigators were contacted to seek unpublished literature. All languages were included. SELECTION CRITERIA: Studies were eligible if they fulfilled all of the four following criteria: 1. Randomized controlled trials, single or double-blind; 2. Participants were patients with Behcet's Syndrome as defined by the International Study Group, 1990 (Int Study Group, 1990); 3. Interventions included any pharmacological therapy compared to placebo or some other pharmacological intervention for the treatment of Behcet's syndrome. 4. Outcome measures included active ocular inflammatory processes, arthritis, mucocutaneous manifestations (oral ulcer, genital ulcer, erythema nodosum), laboratory changes and major events such as adverse effects and death. DATA COLLECTION AND ANALYSIS: The 32 potentially relevant references were assessed by two independent reviewers (MA, AS) according to the inclusion criteria. Ten trials fit the inclusion criteria and were included in this review. From the 10 included trials, data were independently extracted by the same two observers and crosschecked. The quality of the included trials was assessed independently by two observers (MA, AS) using a validated scale (Jadad 1996). For dichotomous measures, the treatment effect for each trial was calculated using a fixed effect model [Peto model (Petitti 1994)]. The weighted mean differences were based, if available, on end-of-trial results. The analysis was conducted separately for each different intervention. Since the trials could not be pooled it was not possible to carry out a sensitivity analysis by quality scores or a subgroup analysis by drug dosages. Because of this lack of comparability across trials and the small number of trials, we could not conduct a heterogeneity test or a funnel plot. MAIN RESULTS: Ten trials and 679 patients were included. The main results were the lack of efficacy of some of the classic treatments for Behcet's syndrome, including colchicine, cyclophosphamide and steroids for eye involvement, azapropazone and colchicine for arthritis and acyclovir, colchicine and topical interpheron for aphthas. The results confirm the protective effects of cyclosporine and azathioprine for eye involvement and benzathine-penicillin for arthritis. REVIEWER'S CONCLUSIONS: We conclude that further randomized, placebo-controlled, double-blind trials should be carried out to compare cyclosporine, azathioprine and benzathine-penicillin versus placebo in order to make the results generalizable and comparable.

Inefficacy of azapropazone in the acute arthritis of Behçet's syndrome: a randomized, double blind, placebo controlled study.

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.

A controlled trial of azapropazone in tinnitus.

A single-blind placebo-controlled trial of azapropazone, a non-steroidal anti-inflammatory drug, is presented in 10 patients with tinnitus. Seventeen variables were assessed by questionnaire and six by a daily diary. In none of these was there a significant difference between placebo and drug. A larger trial is probably therefore not justified.

A comparison of azapropazone and aspirin for pain relief following dental extractions.

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.

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.

Persistent cardioprotection by azapropazone in a canine model of coronary artery thrombosis and thrombolysis.

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.

Myocardial cytoprotective efficacy of azapropazone in a swine model of regional myocardial ischemia/reperfusion injury.

The purpose of the present study is to determine the myocardial cytoprotective efficacy of azapropazone (AZA) on regional myocardial function in anesthetized swine model of regional myocardial ischemia/reperfusion injury. AZA was administered (100 mg/kg, i.v.) 15 minutes prior to reflow. The left anterior descending (LAD) coronary artery occlusion was maintained for a total of 30 minutes and then reperfused for 120 minutes. The effects of AZA on regional segmental shortening (% SS) as well as on neutrophil migration were examined in the (proximal) central and border (distal) zones within the area at risk (AAR). AZA reduced the incidence of myocardial fibrillation which occurred in some animals during the LAD occlusion/reperfusion periods. AZA produced a significant recovery of left ventricular segmental shortening (% SS) in the border, but not in the central zones within the AAR. No significant differences in the hemodynamic parameters were observed between the AZA (n = 14) and the saline-treated (n = 17) groups. AZA produced a significant inhibition of neutrophil migration (as evident from the decrease in myeloperoxidase activity) into epi- and endocardium central and border zones within the AAR. It is concluded that AZA may elicit its cardioprotection in moderately but not in severely injured myocardium by inhibiting the neutrophil migration.

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.

[Post-traumatic edema as a limiting factor in early functional treatment measures and its pharmacodynamic modification]. / Das posttraumatische Odem als begrenzender Faktor frühfunktioneller Behandlungsmassnahmen und seine pharmakodynamische Beeinflussbarkeit.

Post-traumatic oedema is a limiting factor of early functional exercise following fractures. A review of drug prophylaxis used in many clinical studies is given. A 30% reduction of oedema development following bimalleolar fractures was achieved with cyclooxigenase inhibitors (azapropazone) and aprotinin. It is pointed out that non-steroidal antiphlogistic drugs inhibit the collagen metabolism during the healing of rat skin-wounds.

Comparative trial of azapropazone and indomethacin plus allopurinol in acute gout and hyperuricaemia.

This study compared the effects of azapropazone and indomethacin plus allopurinol in the management of acute gout and hyperuricaemia. A group of 93 patients predominantly based in general practice were randomly allocated to the two treatment regimens (azapropazone (days 1-225) or indomethacin (1-28) followed by allopurinol (29-225)) on a double-blind double dummy basis. Azapropazone produced a substantial reduction in serum uric acid levels by day 4 compared with day 1 (P<0.002) and was superior to indomethacin with regard to recorded levels of serum uric acid at day 4 (P<0.01) and day 28 (P<0.05). From day 28 onwards allopurinol produced and azapropazone maintained similar reductions in serum uric acid. Both treatments rapidly controlled the initial acute attacks of gout and both produced side effects similar in frequency and nature. Fewer breakthrough attacks of gout occurred in the azapropazone group (12) than the indomethacin/allopurinol group (21).Although the results achieved in both treatment groups were similar it has been shown that azapropazone is effective monotherapy for controlling both acute attacks of gout and hyperuricaemia.

Effect of treatment on erythrocyte phosphoribosyl pyrophosphate synthetase and glutathione reductase activity in patients with primary gout.

The activities of erythrocyte phosphoribosyl pyrophosphate (PRPP) synthetase and glutathione reductase (GTR) were studied in 26 patients with primary gout who were receiving no treatment or treatment with either allopurinol or azapropazone, and compared with the activity in a group of healthy controls. The activity of PRPP synthetase was significantly higher in the gout group and was not influenced by either drug. No significant difference in the activity of GTR was observed. The failure of either drug to suppress the increased activity of PRPP synthetase associated with gout is discussed.