Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma.

BACKGROUND: The aim of this study was to compare the efficacy and safety of once-daily ciclesonide, a new-generation, on-site-activated, inhaled corticosteroid, with once-daily budesonide in persistent asthma. METHODS: Eligible patients requiring budesonide or equivalent 320-640 microg (ex-mouthpiece, equivalent to 400-800 microg; Turbohalertrade mark) daily entered a 2-week baseline, and then a 2- to 4-week pretreatment period (budesonide 1280 microg/day; ex-mouthpiece, equivalent to 1600 microg/day). Patients with an increase in forced expiratory volume in 1s (FEV1) of 7% or 0.15 L were randomised to ciclesonide 320 microg (ex-actuator, equivalent to 400 microg ex-valve) via a hydrofluoroalkane-metered dose inhaler (HFA-MDI) without a spacer or budesonide 320 microg once daily in the morning for 12 weeks. Change in FEV1 was the primary endpoint. RESULTS: In all, 359 patients were randomised. The FEV1 and forced vital capacity (FVC) decreased by 0.18 and 0.12L, respectively, in the ciclesonide group, and by 0.23 and 0.21L in the budesonide group. For FEV1, ciclesonide was noninferior and numerically superior to budesonide. For FVC, ciclesonide was statistically superior to budesonide (P=0.010). Asthma symptom scores were comparable; the median percentage of symptom-free days was significantly higher for ciclesonide (43.6%) versus budesonide (25.8%) (P=0.017). Rescue medication use decreased significantly only for ciclesonide patients (P=0.009). Frequency of adverse events was low in both groups. CONCLUSION: Ciclesonide 320 microg once daily by HFA-MDI without a spacer was at least as effective as budesonide 320 microg once daily in persistent asthma.

Biological effects of the respirable dusts from ore mines.

The biological effects of ore dusts were examined on peritoneal macrophages in vitro and on rat lung in vivo. The methylene blue adsorption of the dust samples, cytotoxicity, and phospholipid and hydroxyproline content of the lung were determined. It was realized that the examined ore samples had cytotoxic effects and from the in vitro results one can get information about the type of damage to be expected in the lung tissue. It is supposed that the examined ore dusts are less dangerous and slower acting than quartz, but they cause progressive fibrosis. The in vivo biochemical experiments do not give information about the type of damage to be expected in lung tissue; and the data on ore, bentonite, and coal do not differ from each other. To determine the typical biochemical changes caused by quartz, we obtain the most valuable information by determination of lung weight and phospholipid, phosphatidylcholine, and hydroxyproline content.

Urinary beta 2-microglobulin and retinol binding protein: individual fluctuations in cadmium-exposed workers.

Urinary retinol binding protein (RBP) and beta 2-microglobulin (beta 2-m) were compared in apparently healthy population groups with and without occupational exposure to cadmium (Cd). The relationship observed in neutral urine was: RBP (micrograms/mmol creatinine) = 0.786 + 0.814 beta 2-m (micrograms/mmol creatinine). This relationship was similar to that reported for patients with various renal diseases [13]. Analysis of urine samples collected weekly from workers exposed occupationally to Cd revealed marked fluctuations, not only in the concentration of the acid-labile beta 2-m but also in the level of the pre-analytically more stable RBP. Therefore, repeated sampling and urine analyses are suggested as means to obtain more reliable data when monitoring Cd-exposed personnel.

Experimental pneumoconiosis due to dusts of ore mines. II.

The effect of dead rock dusts from a Hungarian ore mine was studied in long term experiments. Histological changes caused by intratracheally introduced respirable mixed rock patterns (Porphyry, Enargite, Scarnic grained- and drill-cuttings) were examined and compared with standard DQ12 quartz samples 3, 6, 12 and 20 months after treatment. All three dusts proved to be fibrogenic, although in different extent. In the case of Porphyry rock patterns also storage type reaction developed. In the case of Scarnic dusts chronic pneumonitis, focal condensation of the reticular network and very mild fibrosis could be observed. The described changes have confirmed that there is a close connection between the destruction of macrophages and the fibrogenic effect. The free quartz content of the dusts, the amount and ratio of "protective" metal oxides (Al-, Ca-, K-, Mg-, Na-oxides) may be responsible for the differences in the histological reaction and the progression of fibrosis.

Short term in vivo method for prediction of the fibrogenic effect of different mineral dusts.

The effect of intratracheal introduction of different metal and mineral dusts and the change in activity of pulmonary acidic phosphatase have been studied as a function of time (72 h, 2 weeks, 1, 12, 20 months). The activity and localization of acid phosphatase were compared with the degree of pulmonary damage caused by dusts. The degree of fibrosis was determined on the basis of the composition of cells and fibres, according to Belt and King's classification. Due to the membrane-damaging effect of DQ 12 silica and mixed dusts (enargite and porphyry rock dusts) an increase in acid phosphatase activity of macrophages could be observed at the end of the first month. At the same time non-fibrogenic or only mild fibrogenic dusts (bentonite, corundum, scarnic rock dust) caused a decrease or disappearance of tissue acid phosphatase activity. It has been stated that there is a very close correlation between the change in pulmonary acidic phosphatase activity and the progression of pulmonary fibrosis due to exposure to mineral dusts. The above investigations have been most useful in predicting the subsequent effect of rock patterns, emphasizing at the same time the importance of in vivo long term experiments.

Comparative histopathological and biochemical analysis of early stages of exposure to non-silicogenic aluminium silicate- and strongly silicogenic quartz-dust in rats.

One group of male CFY rats was given bentonite with high aluminium silicate content, the other group was given quartz dust, intratracheally. It has been stated that between 12-72 hours after the dust-exposure, the histological reactions developing upon the effect of non-silicogenic bentonite and silicogenic quartz are identical. Similarly in both groups lipid and phospholipid content of the lung shows a slight increase; the composition of phospholipids does not alter due to the effect of the two dusts. Between 12-72 hours after the exposure to both dusts the inflammatory response characterizing the histological reaction consists mainly of leukocytes; while between 48-72 hours macrophages appear in large numbers. The dust particles are swallowed both by leukocytes and macrophages. The confluating bronchopneumonia developed at the end of the 72nd hour is characterized by necrosis. Ninety days after exposure, bentonite causes storage-focal tissue reaction and quartz produces progressive pulmonary fibrosis; due to the effect of quartz, the lipid and phospholipid content of the lung significantly increases, the ratio of phospholipid fractions alters; bentonite does not increase the amount of pulmonary lipid and phospholipid. On the basis of the strong aldehyde bisulphite-toluidine blue (ABT) positivity of the macrophages containing bentonite, it may be assumed that the bentonite particle surface has an oriented polysaccharide and/or protein coat released from necrotized leukocytes, which protects the macrophage from the strong cytotoxic (necrotizing) effect of bentonite.

Analysis of aluminium-silicate storage foci in the lungs.

A single dose of 60 mg bentonite dust of 0-2 microns particle size suspended in physiological saline was given to CFY rats intratracheally. The effect of bentonite on the lungs was investigated by electron microscope and electron beam X-ray microanalysis 3 and 6 months later. Two cell types were observed within the so-called bentonite storage foci: the majority of the cells building up the storage foci were dark (type I), while the other cells, especially on the periphery of the foci were light with vacuolized cytoplasm (type II). The type I cells contain inclusions consisting of electron dense and electron lucent layers with high Si and Al content, while type II cells contain only small amounts of Al and Si. The inclusions lying with or without a coating, limiting lamella in the cytoplasm were shown to be bentonite deposits on the basis of their structure and composition. Both cell types derive from macrophages, are poor in organelles and exhibit minimal mitotic activity. The bentonite clearance of the storing cells is supposed to be relatively long.

Experimental pneumoconiosis due to dusts of ore mines, I.

Male CFY rats were injected into their trachea with a suspension of dust of ore mine dead rock of high quartz content and mixed composition (particle size: 0-60 micrometers). Three and six months after treatment, foreign body granulation and after twelve months a non-fibrotic diffuse lung disease was seen in the animals. After twelve months of exposure, non-specific, mature sinus histiocytosis and small focal epitheloid cell reaction were found to develop in the cervical, lung-hilar and retroperitoneal lymph nodes. The histopathological changes were compared with those seen in experimental silicosis induced by DQ12 quartz. It is concluded that the hazardous effect of industrial dusts is not identical with their fibrogenic effect.

Necrotropic protective effect of Ca-Mg gluconolactate on allyl alcohol-induced liver necrosis in rats.

The prevention of liver damage in rats intoxicated with allyl alcohol was attempted with 5 per cent Ca--Mg gluconolactate in reiterated doses. This preparation prevented or reduced liver necrosis only in the presence of spleen: splenectomy annihilated the effect of Ca--Mg gluconolactate.

Studies on the effect of quartz, bentonite and coal dust mixtures on macrophages in vitro.

The effect of quartz, bentonite and coal dusts as well as the effect of the artificial mixture of these dusts on TTC reduction and extra-and intra-cellular lactate dehydrogenase activity in peritoneal rat macrophages was determined in vitro. The cell-membrane-damaging effect of quartz caused a significant extracellular release of lactate dehydrogenase. Bentonite caused no extracellular enzyme release, which leads us to believe that the biological effect of this dust is shown by decrease in intra-cellular lactate dehydrogenase activity. TTC reduction was inhibited equally by quartz and qentonite. In mixtures of quartz (60%)-bentonite (40%) dust the specific effect of quartz was inhibited by bentonite in vitro and also in vivo. We obtained the same results with coal-quartz-bentonite dust mixtures in vitro. Our experiments show that comparison of the biological effects of artificial dust mixtures and airborne dust samples is justified, and prove that performing various examinations simultaneously give fuller particulars on the probable biological effect of mineral dusts.