Comparison of the efficacy and safety of high doses of beclometasone dipropionate suspension for nebulization and beclometasone dipropionate via a metered-dose inhaler in steroid-dependent adults with moderate to severe asthma.

Nebulization for the administration of high doses of inhaled corticosteroids can benefit steroid-dependent asthmatics. The objective of this double-blind, double-dummy, multicentre, randomized, parallel-group study was to compare the efficacy and safety of high-dose corticosteroids given by nebulization or metered-dose inhalation in adult patients with asthma. Following a 2-week run-in period, 124 patients, aged 18-70 years, with moderate to severe asthma treated with high-dose inhaled steroids were randomized to one of two treatment groups for 12 weeks: beclometasone dipropionate (BDP) suspension for nebulization 3,000-4,000 microgday(-1) b.i.d. given via a nebulizer (n = 63), or BDP spray 1,500-2000 microgday(-1) b.i.d. given via a metered-dose inhaler (MDI) plus spacer (BDP MDI) (n = 61). Comparable improvements over baseline, which were statistically significant in most cases, were reported at study end for the two treatment groups in the various efficacy parameters evaluated (pulmonary function tests, clinical symptoms scores, and the use of rescue salbutamol). The primary efficacy endpoint was morning pulmonary expiratory flow rate (PEFR). For the intent-to-treat population, in the BDP nebulization group mean morning PEFR increased statistically significantly from 308.7 +/- 107.81 min(-1) to 3 19.2 +/- 104.01 min(-1) while in the BDP MDI group the increase was from 301.5 +/- 94.71 min(-1) to 309.3 +/- 86.71 min(-1). The two treatments were equally well tolerated.A total of 19 patients in each group reported adverse events during the treatment period, and these were generally mild-moderate in severity. In conclusion, the results of this study demonstrate that BDP suspension for nebulization 3,000-4,000 microg day(-1) given via a nebulizer and BDP spray 1,500-2,000 microg day(-1) given via an MDI plus spacer are equally effective, with an acceptable safety and tolerability profile, when used in steroid-dependent adult patients with moderate to severe asthma.

Comparison of hydrogen peroxide generation and the content of lipid peroxidation products in lung cancer tissue and pulmonary parenchyma.

Lipid peroxidation, as a well-known index of reactive oxygen species activity, not only in lung biochemistry, is an oxidative process associated with membrane lipid destruction. Also, the oxidative modification of nucleic acids by reactive oxygen species is of remarkable biological importance as it may contribute to malignant conversion, but its exact role in lung cancer biology is still not clear. Our study aimed to investigate the level of lipid peroxidation ex vivo in tumour tissue and lung parenchyma obtained from patients with lung cancer. Forty-two patients with lung cancer were enrolled into the study. During a surgical resection, tumour tissue and lung parenchyma were obtained and concentration of lipid peroxidation products, thiobarbituric acid-reactive substances and Schiff bases, and spontaneous generation of hydrogen peroxide, were measured. The concentration of thiobarbituric acid-reactive substances (P<0.001) in the tumour tissue was higher than that in lung parenchyma. In small cell lung cancer as well as in squamous cell carcinoma patients, a positive correlation between spontaneous generation of hydrogen peroxide in tumour tissue and clinical stage (r = 0.43; r = 0.46; respectively) was found. Our results prove enhanced lipid peroxidation in cancer tissue as compared with matched-lung parenchyma. In small cell lung cancer and squamous cell carcinoma patients, the high level of oxidative stress, expressed as a spontaneous generation of hydrogen peroxide in tumour tissue, was associated with clinical progression of tumour's stage.

Equivalent asthma control and systemic safety of inhaled budesonide delivered via HFA-134a or CFC propellant in a broad range of doses.

The aim of the present study was to demonstrate an equivalent asthma control and safety of inhaled budesonide 200 microg unit-dose via a spacer device (Jet Spacer, Chiesi Farmaceutici S.p.A.) given with an HFA-134a or CFC propellant in stable patients treated with inhaled corticosteroids. A total number of 270 patients, 134 in the HFA-134a group and 136 in the CFC group, completed a 2-week run-in period and were then randomised to receive a daily dose of inhaled budesonide (low dose: 400 microg, medium dose: 800 microg, high dose: 1200 or 1600 microg), defined on the basis of the dose of previous inhaled steroids given twice daily for 12 weeks. Morning and evening PEFR, intake of rescue salbutamol, number of day-time and night-time asthma attacks, number of night-time awakenings due to asthma and clinical symptoms were recorded daily by patients on diary cards. Pulmonary function tests (FEV1, FVC, PEFR and MEF50) and vital signs were measured at the clinics at study entry, at the start of treatment and after 2, 4, 8 and 12 weeks thereafter. Morning serum cortisol (8.00-10.00 AM) was measured at baseline and in the final visit. Adverse events and vital signs were recorded throughout the total study period. Small increases vs. baseline for lung function (more markedly in the high-dose subsets) and significant decreases of symptoms and use of rescue salbutamol were similarly observed in both groups. Equivalence was demonstrated for the primary endpoint morning PEFR (difference between means = -1.51 l/min; 95% CI: -9.40-6.37 l/min; pre-defined limits: +/- 42.16 l/min, i.e. +/- 10% of the reference LSM) as well as for evening PEFR and FEV1, both in the ITT population or on a per-protocol basis. No statistically significant differences between groups were observed in any of the other efficacy variables. A similar proportion of drug-related adverse events was observed in the two groups, without drug-related serious events in either group. No evidence of adrenal depletion was also noted with both propellants. In conclusion, the budesonide HFA-134a formulation given with a spacer device provided an equivalent asthma control with that of a corresponding CFC product, when administered in stable patients treated with inhaled corticosteroids in a broad range of daily doses. The use of the new propellant did not modify the safety profile of inhaled budesonide.

Aspirin-induced urticaria--a clinical study.

This paper describes the clinical characteristics of patients with aspirin-induced urticaria. The group of 71 patients (49 women and 22 men), with a mean duration of symptoms of 32.5 years, underwent allergological, laryngological and histamine dihydrochloride inhalation tests. Nasal polyps were found in 2 patients (2.8%), atopic disease in 23 (32.3%) and at least one feature of atopy in 37 (51.9%). Forty-nine patients (69%) suffered from urticaria which was not associated with aspirin. In 22 patients, urticaria developed solely due to aspirin. Urticaria not associated with aspirin has been present from 2 weeks to 30 years before the onset of sensitivity to aspirin. The authors conclude that aspirin-induced urticaria results from two different concomitant phenomena, i.e. sensitivity to aspirin and urticaria not associated with ingestion of the drug.

Urticaria/angioedema-type sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs. Diagnostic value of anamnesis and challenge test with acetylsalicylic acid.

The aim of this study was to determine the value of challenge tests with acetylsalicylic acid in the diagnosis of ASA-induced urticaria. The study was performed in 71 patients with suspected urticaria/angioedema-type sensitivity to ASA. Anamnesis confirmed sensitivity in 67 patients (94.4%) and showed that sensitive patients usually suffered from extensive urticaria (37 patients, i.e 55.5%) after ingestion of ASA. Eight patients (12%) reacted with loss of consciousness and 4 (6.0%) with edema of the larynx. Oral challenge test with acetylsalicylic acid was performed in 53 patients, in 49 (92.4%) of whom it was positive. Threshold doses of acetylsalicylic acid ranged from 40 to 300 mg. In 11 patients, the test was repeated and in 8 it was performed 3 times. It was observed that both the threshold acetylsalicylic acid doses and the time of appearance of sensitivity symptoms were variable. All ASA-sensitive patients reacted to indomethacin in a similar manner as to ASA. Paracetamol, on the other hand, was well tolerated by all 25 evaluated patients with urticaria/angioedema-type sensitivity to ASA.

The value of C1 esterase inhibitor in patients with aspirin-sensitive urticaria.

The aim of the study was to evaluate the concentration and activity of C1 esterase inhibitor (C1 INH) in patients with aspirin-sensitive urticaria. C1 INH deficiency is the basis of hereditary angioneurotic edema. The study was performed on 32 subjects with aspirin-sensitive urticaria. The value of C1 INH in examined patients was the same as in the control group. There seems to be no coexistence of aspirin-sensitive urticaria and C1 esterase inhibitor deficiency.

Tolerance to aspirin in aspirin-sensitive asthmatics. Methods of inducing the tolerance state and its influence on the course of asthma and rhinosinusitis.

Aspirin-sensitive asthma is a serious clinical problem, frequently involving dramatic exacerbation and sometimes even death after the accidental ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). The majority of such asthmatics usually suffer from chronic rhinosinusitis and nasal polyps as well, and almost half of them from headaches. Widal et al. in 1922, and later, Zeiss and Lockey were able to elicit tolerance to aspirin (ASA). In all the studies performed so far, tolerance to ASA was achieved by giving double threshold ASA doses every day or every few hours. This method elicited severe dyspnea and sometimes pronounced extrabronchial sensitivity symptoms. From our previous studies, it appeared that the smaller the aspirin dose, the weaker the sensitivity symptoms, and that it is possible to induce tolerance after eliciting only very slight sensitivity reactions. Based on this observation, we elaborated a new method of eliciting aspirin tolerance by the daily administration of gradually increasing doses of aspirin starting with subthreshold doses. Applying this method, we achieved tolerance to aspirin without any adverse reactions. The patients in a tolerance state to ASA also tolerated well other NSAIDs, i.e. indomethacin and diclofenac. It is possible to maintain a tolerance state for a long time by the administration of ASA at proper intervals. It was shown that such a procedure may have a beneficial influence on the course of asthma and rhinitis. In our opinion, inducing and maintaining aspirin tolerance in aspirin-sensitive asthmatics is indicated in the following situations: 1) the need to treat coexisting rheumatic diseases; 2) the need to treat coexisting intractable headaches; and 3) the need for symptomatic treatment of ASA-sensitive asthma and rhinitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin-induced neutrophil chemotactic activity (NCA) in patients with aspirin-sensitive urticaria after desensitization to the drug.

The increase in neutrophil chemotactic activity (NCA) is related to mast cell degranulation. This study was performed in 10 patients in whom aspirin-induced urticaria was connected with increased NCA. A state of tolerance to aspirin (ASA) was achieved by administering incremental doses of acetylsalicylic acid. In none of the examined patients was an increase in NCA observed after 600 mg of ASA given after desensitization. The authors conclude that in patients with ASA-induced urticaria, mast cell degranulation does not occur after ASA desensitization.

Enhanced lipid peroxidation in cancer tissue homogenates in non-small cell lung cancer.

The oxidative modification of nucleic acids by reactive oxygen species may lead to malignant conversion, but its exact role in lung cancer biology is still not clear. Lipid peroxidation, a well-known index of free radicals activity, is a process of oxidative polyunsaturated acids destruction. Our study was aimed to investigate the level of lipid peroxidation ex vivo in tumor tissue and lung parenchyma obtained from patients with non-small cell lung cancer. Thirty-two patients with lung cancer (including 19 with squamous cell lung cancer) were enrolled in the study. During a surgical resection, tumor tissue and lung parenchyma were obtained and the concentration of lipid peroxidation products, i.e. conjugated dienes and lipid hydroperoxides, measured. In the whole group of patients the concentrations of conjugated dienes and lipid hydroperoxides in the tumor tissue were higher than those in lung parenchyma (1.008 +/- 0.503 A233 nm vs. 0.717 +/- 0.283 A233 nm; p < 0.05 and 0.109 +/- 0.062 A532 nm vs. 0.102 +/- 0.087 A532 nm; p < 0.05, respectively). Similar results were obtained in squamous cell carcinoma patients (0.975 +/- 0.348 A233 nm vs. 0.708 +/- 0.300 A233 nm; p > 0.02 and 0.094 +/- 0.029 A532 nm vs. 0.080 +/- 0.071 A532 nm; p < 0.05, respectively). In both groups of patients, a positive correlation between concentration of conjugated dienes in tumor tissue and clinical stage (R = 0.45; R = 0.52; p < 0.05, respectively) was found. Our results confirm the enhanced lipid peroxidation in cancer tissue as compared with matched lung parenchyma. Additionally, a higher level of oxidative stress, expressed as the concentration of conjugated dienes in tumor tissue, was associated with clinical progression of the tumor.

[Urticaria (angioedema type sensitivity) caused by aspirin]. / Pokrzywkowo-obrzekowa postac nadwrazliwosci na kwas acetylosalicylowy.

The paper deals with urticaria/angioedema type of sensitivity to aspirin and other nonsteroidal antiinflammatory drugs. The clinical, alergological studies and usefulness of the available diagnostic methods are presented. The pathomechanism of bronchospastic and urticarial type of sensitivity to aspirin is also discussed.

[Pathogenesis of chronic urticaria]. / Patogeneza przewleklej pokrzywki.

This article is a review of the role of mast cells and other inflammatory cells in pathogenesis of chronic urticaria. The role of histamine in pathophysiology of chronic urticaria has been established but interaction between IgE-bound mast cells and allergen is unlikely to be the mechanism by which histamine release occurs. The authors present some factors trigger mast cell degranulation and mediator release as histamine releasing factor (HRF) generating by lymphocytes and IgE autoantibodies against mast cell and basophil IgE receptors.

[Histamine as a mediator of allergic inflammation]. / Histamina jako mediator zapalenia alergicznego.

The allergic process is believed to consist of two phases: early and late. The early phase reaction is mainly induced by histamine released from mast cells. Histamine binding specific cell receptors produces clinical allergic symptoms. This mediator also activates neutrophils and eosinophils as well as being a chemoattractant for these cells. Histamine increases IL-8 level and evokes leukocyte rolling on endothelial cells. Thus histamine participates in both early and late-phase allergic responses.

[Second generation topical antihistaminics]. / Leki przeciwhistaminowe drugiej generacji o dzialaniu miejscowym.

The article presents two topical antihistaminics: levocabastine and azelastine. Most attention is paid to discussing the pharmacokinetics and antihistamine, antiallergic and antiinflammatory activities of these drugs. Their clinical usefulness in allergic rhinitis and conjunctivitis is also presented. Finally the authors describe the adverse reaction observed after administrating of topical antihistaminics.

[The effect of new H1-receptor antagonists on cardiovascular system]. / Wplyw leków przeciwhistaminowych drugiej generacji na serce.

The authors present effects of new H1-receptor antagonists--terfenadine and astemizol on cardiovascular system in humans. The role of interactions between terfenadine and astemizol and other drugs is underlined. Effects of hepatic and heart diseases as well as astemizol and terfenadine overdose on their pharmacokinetics are also showed.

[The antiallergic and anti-inflammatory effects of the second generation of antihistamines]. / Przeciwalergiczne i przeciwzapalne dzialanie leków przeciwhistaminowych drugiej generacji.

The authors present the pathomechanism of allergic diseases and the role of adhesion molecules in this process. The antiallergic and antiinflammatory activities of selective antagonists of H1 receptors are presented.

[Evaluation of the relationship between the clinical course of severe asthma and ventilatory parameters]. / Ocena zwiazków miedzy klinicznym przebiegiem ciezkiej astmy oskrzelowej a wskaznikiem wentylacji.

The aim of the study was the assessement of relations between the clinical symptoms of asthma, ventilatory parameters and nonspecific bronchial hyperresponsiveness. 22 patients with severe asthma, 12 females and 10 men, aged 43-68 years (mean 56) were observed for two years. The duration of asthma ranged from 6 to 38 years (mean 18). All the patients were treated with inhalatory steroids in dose 800-1200 mg. Three months before entering the study the patients had no exacerbation or respiratory tract infection. Throughout the study diary cards were filled and the symptoms were recorded on 0-4 scale. PEF was measured two times a day, the highest value noted. Spirometry and reversibility tests were performed. On the last day patients underwent histamine challenge test. Data from four weeks were analyzed statistically. The significant correlation was established between PEF variability and clinical symptoms scores, both mean and measured in the last day of the study. The relationship between mean PEF variability and bronchial hyperresponsiveness was also observed.

[Pulmonary tuberculosis in families of patients with bacteriologically positive pulmonary tuberculosis]. / Gruzlica pluc w rodzinach osób chorych na gruzlice pluc potwierdzona bakteriologicznie.

The aim of the study was to carry out analysis of pulmonary tuberculosis occurrence in multimember families in which at least one person was suffering from pulmonary tuberculosis bacteriologically confirmed (BK+). The study was based on clinical examination, chest-X-rays analysis and outpatients clinic files. The initial number of patients suffering from tuberculosis BK(+) was 70, therefore 268 people from 70 families were included in the study. In 48 (70%) of families there was only one case of pulmonary tuberculosis BK+ throughout 5 years of observation. In the remaining 22 (30%) of families at least one more case of pulmonary tuberculosis was recorded. 60% of those cases concerned a spouse. In 10% of families where one person had relapses of tuberculosis BK+, within one year an another case of pulmonary tuberculosis bacteriologically positive or negative was confirmed.

[Familial occurrence of tuberculosis--a report of vice cases in a seven-person family in a period of 14 years]. / Rodzinne wystepowanie gruzlicy pluc--opis pieciu przypadków w siedmioosobowej rodzinie w okresie 14 lat.

Tuberculosis in five persons among the seven family members is reported. The main reasons for occurrence of tuberculosis in the majority of the family members were alcoholism and non-compliance with doctor's recommendations, then resistance of tubercle bacilli to antituberculous drugs, due to the above mentioned reasons. Even chemoprophylaxis in two of the family members did not protect then from the disease.

[The effect of second generation histamine antagonists on the heart]. / Wplyw leków przeciwhistaminowych drugiej generacji na serce.

The review summarizes recent progress in the study of the cardiac actions of second--generation antihistamines. Terfenadine and astemizole, two antihistamines of the second generation, are in vitro potent blockers of potassium channels (K+). It has been considered to be responsible for QT prolongation of the electrocardiogram and life--treating ventricular tachycardias called torsades de pointes. Loratadine and descarboethoxyloratadine, the major metabolite of loratadine were studied on a human cardiac K+ channel (hKv 1.5) cloned from human ventricle. Parent compound and its metabolite in high concentration blocked hKv1.5 channels. However, loratadine (10 mumol/L) failed to inhibit HERG potassium channel and HERG K+. Ebastine also inhibit potassium channels, cloned human Kv 1.5. Cetirizine was completely devoid of any inhibitory action on HERG K+ channels in concentration up to 30 mumd/L. On the other hand terfenadine and astemizole effectively blocked HERG K+ channels with nanomolar affinities (330 and 480 nmol/L, respectively), whereas loratadine was about 300-fold less potent. Fexofenadine--the major metabolite of terfenadine, does not block either HERG or Kv1.5. The quinea pig model (in vitro) revealed that only terfenadine, astemizole and ebastine produced significant QT interval prolongation and arrhythmogenic effects. The other nonsedating antihistamines including cetirizine, loratadine and the major metabolite of ebastine (carabastine), terfenadine (feksofenadine) and astemizole (norastemizole) were devoid of QT interval prolongation and other adverse ECG effects.

[Atopy with recurrent wheezy bronchitis in children]. / Atopia w nawrotowym obturacyjnym zapaleniu oskrzeli u dzieci.

Childhood asthma and wheezy bronchitis are the most frequent chronic diseases of childhood. Unfortunately their clinical symptoms are similar--which makes it difficult to distinguish between the two, and therefore decide on proper treatment of patients. The aim of the study was to establish the parameters leading to right diagnosis. The study was performed in 50 children aged 3-7 years with recurrent wheezy bronchitis. All patients underwent allergological examinations (skin tests with inhaled allergens, personal and family history and serum total and specific IgE levels). 42 of them were tested for ventilatory parameters with bronchodilatation test. Three features of atopy were found in 21 (42%) patients, two features in 7 (14%) patients. In 31 (62%) children at least one feature of atopy was shown. 7 (17%) of the examined children had significant bronchodilatation after salbutamol inhalation. Finally in 24 (48%) of children suffering from wheezy bronchitis, bronchial asthma was diagnosed. The diagnosis was confirmed by antiasthma tic treatment with cromones or inhaled corticosteroids. In great majority (88%) of patients bronchial asthma was atopic. In 23% wheezy bronchitis children not diagnosed with bronchial asthma features of atopy were observed. They are of bronchial asthma risk group.