Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics.

From bronchoprovocation studies and investigations of the acute effects of drugs that inhibit leukotrienes (LT), the hypothesis has emerged that leukotrienes are important mediators of airway obstruction and other symptoms in aspirin-intolerant asthma (AIA). However, it has yet not been shown if subjects with AIA respond favorably to clinical treatment with leukotriene inhibitors. Therefore, in a double-blind placebo-controlled crossover study, we examined the effects of 6 wk of treatment with the leukotriene-pathway inhibitor zileuton (600 mg, four times daily) in 40 patients with well-characterized AIA. The treatment was added to existing therapy, which included medium to high doses of inhaled (average daily dose 1,030 microg of beclomethasone or budesonide) or oral glucocorticosteroids (4 to 25 mg/d) for all but one of the patients. On top of this treated baseline, there were no significant effects of adding placebo, indicating that their asthma was kept relatively stable. However, there was an acute and chronic improvement in pulmonary function after treatment with zileuton, expressed both as increased FEV1 from baseline compared with placebo, and higher morning and evening peak expiratory flow rate (PEFR) values on zileuton treatment compared with placebo. The improvements occurred despite lower use of rescue bronchodilator with zileuton. Zileuton also diminished nasal dysfunction, which is one of the cardinal signs of AIA. There was a remarkable return of smell, less rhinorrhea, and a trend for less stuffiness and higher nasal inspiratory flow during treatment with zileuton. Zileuton caused a small but distinct reduction of bronchial hyperresponsiveness to histamine and inhibited aspirin-induced bronchoconstriction. Zileuton inhibited urinary excretion of LTE4 but did not change airway reactivity to inhaled LTD4, supporting that zileuton specifically inhibited leukotriene biosynthesis. The findings indicate that leukotrienes are important mediators of persistent airway obstruction and chronic nasal dysfunction in AIA. The study also suggests that addition of a leukotriene pathway inhibitor such as zileuton may bring about greater control of asthma than what is achieved by treatment with medium to high doses of glucocorticosteroids alone.

[Subclinical pro-thrombotic state in a relapse of Behcet's disease--case report]. / Subkliniczny stan prozakrzepowy w zaostrzeniu choroby Behceta--opis przypadku.

A patient, aged 34, with a relapse of Behcet's disease (BD) showed laboratory features of enhanced coagulation activation without any symptoms of arterial or venous thrombosis. Elevated levels of thrombin-antithrombin III complexes (TAT), prothrombin fragments 1 + 2 (F1 + 2), associated with impairement of fibrinolysis were found. Total fibrinolytic activity, measured on fibrin plates, plasma concentration of tissue-type plasminogen activator (tPA:Ag) and plasmin-alpha 2-antiplasmin complexes (PAP) were low, whereas plasminogen activator inhibitor 1 concentration (PAI-1:Ag) was elevated in comparison with normal values. There intravenous 500 mg doses of cyclophosphamide, given on day 0, 7 and 50, resulted in a marked clinical improvement. This was accompanied by the normalization of augmented thrombin generation and increased fibrinolytic activity. This is the first report to show prothrombotic tendency in a relapse of Behcet disease and beneficial effect of cyclophosphamide therapy on haemostatic abnormalities. A degree of activation of coagulative and fibrinolytic system seems to be of importance in the pathogenesis of Behcet's disease, and monitoring of hemostatic parameters could be helpful in clinical assessment.

Treatment of steroid-dependent bronchial asthma with cyclosporin.

The treatment of chronic severe asthma is unsatisfactory for many patients. The aim of the study was to determine the effects of treatment of steroid-dependent asthma with cyclosporin. We performed a double-blind, placebo-controlled, randomized, parallel group trial on the effect of cyclosporin on pulmonary function, asthma severity and tapering of prednisone in 34 steroid-dependent asthmatics (mean oral prednisone dose: 16 mg.day-1). The study consisted of: 1) baseline period (12 weeks); 2) experimental period divided into two parts: Part I (12 weeks) cyclosporin or placebo treatment; Part II (22 weeks) cyclosporin or placebo treatment and oral prednisone reduction; and 3) follow-up observation (8 weeks). Asthma symptoms score, pulmonary function tests (daily peak expiratory flow (PEF) and bi-weekly forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow (MEF50), biochemical profile and blood cyclosporin levels were monitored throughout the study. Following cyclosporin administration, a slight beneficial effect on some subjective parameters of asthma severity was observed. At the same time, no beneficial effect on pulmonary function was noted. The time trends analysis of mean daily prednisone doses between the treatment groups revealed a statistically significant difference indicating that, during prednisone reduction, cyclosporin seemed to be slightly more efficient than placebo in reducing the requirement for systemic corticosteroid, even though the steroid reduction was accompanied by slight impairment of some pulmonary function. However, there was no significant difference in the final dose reduction between the treatment groups. These data and the known toxicity of the drug suggest a limited place for cyclosporin treatment in steroid-dependent bronchial asthma.

Cyclosporin for steroid-dependent asthma.

We used cyclosporin to treat 12 adult patients with severe bronchial asthma who had been on systemic steroids for an average of 16 years. During the baseline period, lasting 4-6 months, therapy with high doses of inhaled beclamethasone, aminophylline and salbutamol was standardized and a minimum necessary dose of systemic steroids was established. After 9 months' treatment with low-dose cyclosporin (average whole-blood trough levels of 105 ng/ml), in six patients the daily dose of oral prednisone could be reduced from mean 30 mg to mean 11 mg, while daily symptom scores and peak expiratory flows improved significantly. This was accompanied by a reduction in exacerbations of asthma. However, in six other patients attempts to taper the steroid doses were unsuccessful, and cyclosporin was stopped after 4 to 7 months. These preliminary results suggest that cyclosporin might be of benefit in some patients with steroid-dependent asthma.