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Biomedical subjects

R Brattsand

Publications and source records attributed to R Brattsand.

At least 55 records · Page 3Linked to original sources
PubMed1988

The anti-inflammatory activity of Ebselen but not thiols in experimental alveolitis and bronchiolitis.

This paper describes the effects of the thiol compounds glutathione and N-acetylcysteine and the seleno-organic agent Ebselen on the development of Sephadex-induced lung edema and cell infiltration in the rat. Neither thiol had any effect upon the development of the edema when administered in large, repeated doses. In contrast, when Ebselen was co-administered with the thiols, there was a dose-dependent inhibition of the development of the edema, but lung weights could not be returned to normal values. However, when the thiols were omitted and Ebselen was administered alone, the development of the edema was totally blocked. In addition, in Ebselen-only treated animals there was a selective inhibition of the infiltration of lymphocytes, basophils and eosinophils into the lung lumen without affecting the populations of macrophages and neutrophils. Again, the Ebselen-induced effect was reduced by coadministration of either thiol. These findings are discussed in terms of the potential mechanism of action of Ebselen in vivo and of the possibility of Ebselen being of therapeutic potential in cases of diffuse pulmonary inflammation in humans.

Animals↗
PubMed1988

Lung and systemic thiol homeostasis during an acute lung inflammation in the rat.

The instillation of Sephadex beads into the lungs of rats induces a sustained, acute inflammatory reaction within the lungs which caused significant increases in whole lung free and total glutathione (GSH) of approximately 30% after 72 h of reaction. Concurrently, levels of free and total cysteine (CySH) were increased by approximately 600% and 300%, respectively. Similarly, extended inflammation raised the intracellular content of free and total GSH in intraluminal cells by approximately 50% whilst causing the accumulation of oxidised CySH in the extracellular lavage fluid. Simultaneously, fluctuative trends were noted in several systemic thiol pools. Liver free and total GSH were shown to fall without alteration to CySH components. In contrast the plasma redox balance of GSH was unaltered but depletions of free and total CySH were noted after 72 h of inflammation. These results are discussed in terms of the occurrence of oxidative stress during acute pulmonary inflammation and the relationship of these observations to systemic thiol homeostasis and observations in other models of oxidant-induced pulmonary toxicity.

Animals↗
PubMed1988

Effects of oral N-acetylcysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers.

Bronchoalveolar lavage (BAL) was performed in fourteen healthy non-smokers and eleven healthy smokers. In smokers BAL was performed before and after eight weeks' treatment with N-acetylcysteine (NAC; 200 mg t.i.d.). Cell number, composition and viability were determined in the BAL fluid. Alveolar macrophages (AMs) were cultured before examination of their phagocytic capacity and their ability to produce leukotriene B4 (LTB4). BAL fluid from smokers contained more cells than that from non-smokers (p less than 0.001). This was mainly attributable to increases in both proportion and absolute number of AMs (p less than 0.001) and to an increase in absolute number of neutrophils (p less than 0.05). However, there was a decrease in proportion of lymphocytes in BAL fluid from smokers (p less than 0.001). Phagocytic capacity of adherent cells and capacity of AMs to generate LTB4 after stimulation with opsonized zymosan (OZy) were decreased in smokers (p less than 0.05 and p less than 0.01 respectively). NAC treatment of smokers did not affect cell number but resulted in an increased proportion of lymphocytes in BAL fluid (p less than 0.05). The phagocytic capacity of AMs was not significantly altered but was improved in five of eleven smokers after NAC treatment. NAC also enhanced the decreased LTB4 secretion by smokers' AMs (p less than 0.05). We conclude that smoking leads to reduced phagocytic capacity and LTB4 secretion of AMs and that oral NAC treatment may improve the function of AMs.

Acetylcysteine↗
PubMed1988

Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: correlation to effects on cellular variables.

Bronchoalveolar lavage (BAL) was performed on eleven healthy smokers before and after eight weeks of oral treatment with N-acetylcysteine (NAC) 200 mg t.i.d. The concentrations of selected eosinophil and neutrophil granule constituents and of selected proteases and protease inhibitors, albumin and endotoxin were determined in the recovered BAL fluid and in plasma or serum samples. In addition, in vitro chemotactic activities for neutrophils and eosinophils were assessed in the BAL fluid. Significant reductions in BAL fluid content of lactoferrin (LF), eosinophil cationic protein (ECP), antichymotrypsin (ACT) and chemotactic activity for neutrophils were recorded after NAC treatment. The levels of other examined markers tended to be reduced or were not affected. In serum/plasma, the concentrations of myeloperoxidase (MPO) and elastase were reduced after NAC treatment whereas concentrations of other constituents examined were unaltered. These data, together with previously reported findings, suggest that oral NAC may influence the activity of "inflammatory" cells in the bronchoalveolar space of smokers.

Acetylcysteine↗
PubMed1987

The effect of acute cigarette smoke inhalation on pulmonary and systemic cysteine and glutathione redox states in the rat.

Inhalation of Tobacco smoke (TS) by rats for 1 h caused significant depletions in the free glutathione (GSH) of homogenate supernatants of whole lung (13.9-8.8 mumol/g protein), lavage cells (2.7-1.7 nmol/10(6) cells) and lavage fluid (1.3-0.4 microM). In each case the depletions were nonrecoverable by dithiothreitol (DTT) suggesting conjugation between GSH and TS-borne electrophiles. Corresponding lung cysteine (CySH) components were unaffected by TS inhalation. In contrast, TS inhalation had no effect on the blood plasma GSH redox balance at various points around the circulation, but was shown to affect those of CySH, causing significant reductions in total CySH in plasma samples obtained both pre- and postpulmonarily. Similarly, the redox status of GSH in homogenate supernatants of whole liver was unaffected by TS inhalation, but there were significant increases in hepatic free CySH. These results indicate that acute TS inhalation increases the oxidant burden on the lungs causing a transient depletion of GSH in a variety of pools. Concurrently, the lungs may possess regulatory mechanism(s) which respond immediately by the uptake of CySH equivalents present in plasma disulfides.

Animals↗
PubMed1987

Human alveolar macrophages from smokers have an impaired capacity to secrete LTB4 but not other chemotactic factors.

The function of alveolar macrophages (AM phi s) was studied in terms of the secretion of various chemotactic factors. Human AM phi s were obtained by BAL from healthy non-smokers and smokers. One of the chemotactic factors was LTB4, an arachidonic acid metabolite of the lipoxygenase pathway. The amount of LTB4 was determined in culture medium, in cell homogenate and in BAL-fluid. The total chemotactic activity for neutrophils was measured in culture medium and in BAL-fluid. AM phi s from smokers showed an impaired secretion of LTB4. The spontaneous secretion in vitro was inhibited by 90% (p less than 0.05) and the stimulated one was blocked by 84% (p less than 0.05). This impairment was not followed by a decrease in total chemotactic activity, indicating the existence of other chemotactic factors than LTB4. Preliminary characterization of the chemotactic activity by gel filtration demonstrated at least four different chemotactic factors. Budesonide inhibited both the release of LTB4 and the total chemotactic activity in medium from stimulated AM phi s.

Bronchoalveolar Lavage Fluid↗
PubMed1987

Intravenous versus intrapulmonary administration of corticosteroids in combination with fluid infusion in experimental septic shock.

Three different routes of corticosteroid administration (intravenous (IV), intratracheal instillation (IT), and aerosol inhalation (AE)) were evaluated for the treatment of an experimental septic shock induced by E. coli, given intraperitoneally. The corticosteroids, dexamethasone and budesonide, were given alone and in combination with 3% albumin infusion. Shock induced a plasma volume loss to 69% of control levels. This was partially prevented by corticosteroids alone, and prevented completely by 3% albumin infusion. The two corticosteroids were identical with respect to prolongation of survival time and hematocrit changes, regardless of the route of administration. Plasma steroid concentrations of budesonide were similar after IT and IV administration. Increasing doses of corticosteroids up to 8 mg/kg significantly prolonged mean survival time from 9 to 13 hours. When antibiotics and 3% albumin infusions were combined, survival time increased to 15 hours. Corticosteroids added to antibiotics and 3% albumin increased 24-hour survival rate from 0 to 60% (p less than 0.001). Intrapulmonary administration of corticosteroids is as effective as the intravenous route, and offers an important alternative, with obvious clinical implications. Further pharmacological modifications of the corticosteroids are necessary in order to evaluate local pulmonary versus the systemic effects.

Administration, Inhalation↗
PubMed1986

Antigen-induced bronchial anaphylaxis in actively sensitized SD rats. Effects of glucocorticoid treatment.

We examined the effects of glucocorticosteroids (GCS) on antigen-induced bronchial anaphylactic reactions (BAR) in SD rats immunized with ovalbumin (OA) and alum. The animals were treated with vehicle, budesonide (BUD), dexamethasone (DEX), or hydrocortisone (HC) at various times before intravenous (i.v.) antigen challenge. The drugs were administered either intraperitoneally (i.p.) or intratracheally (i.t.); the BAR was elicited by a low or by a high challenge dose of antigen. A BAR elicited by a low challenge dose of antigen was reduced in a dose-dependent way by all GCS after i.p. administration; at 1 mg/kg, BUD and DEX significantly reduced BAR and at 50 mg/kg all three of the examined compounds inhibited the BAR by 50% or more. For BUD, maximum effect was recorded when it was given 12 h before test. There was only a slight variation in the inhibitory effects of the GCS with immunization conditions of test animals. I.t. instillation of the drugs did not markedly increase their inhibitory capacity as compared to i.p. administration. BAR elicited by a high antigen dose was at best marginally affected by the GCS when given either i.p. or i.t. Thus, antigen-induced airway reactivity in rats can be reduced by GCS treatment provided that this is performed sufficiently long before the test and that the challenge dose of antigen is not too high.

Acetophenones↗
PubMed1986

Antigen-induced bronchial anaphylaxis in actively sensitized SD rats. Effects of local treatment with anti-asthmatic drugs.

We studied the effects of anti-asthmatic and anti-inflammatory drugs on antigen-induced bronchial anaphylactic reactions (BAR) in Sprague Dawley (SD) rats immunized with ovalbumin (OA) and alum. The animals were treated locally (intratracheal instillation (i.t.) or by aerosol) with terbutaline (TERB), disodium cromoglycate (DSCG), theophylline (THEO), the xanthine derivative 3,7-dihydro-1,8-dimethyl-3-phenyl-1H-purine-2,6-dione (D4026), budesonide (BUD) or dexamethasone (DEX) at various times before intravenous (i.v.) challenge with OA. The BAR was elicited by giving a low dose of OA. When the response to that challenge had levelled an additional high dose of antigen was given. Previous work had shown that TERB, DSCG, and D4026 given systemically (i.v.) at a suboptimal dose, had a better inhibitory efficacy when the animals were challenged with a low antigen dose late (6 weeks) than when challenged early (2-3 weeks) after immunization. We show here that such a difference in efficacy is not recorded after local treatment. Moreover, each of the drugs inhibited BAR to the same extent after i.t. as after i.v. treatment. Potent drugs like TERB and D4026 seemed to show similar efficacy when given either i.t. or by aerosol, whereas less potent drugs like DSCG and THEO were less effective when given by aerosol. In a previous study, we showed that the inhibitory capacity of glucocorticoids (GCS) on the BAR did not vary with sensitization conditions of the rats, BUD and DEX showed the same inhibitory capacity after intraperitoneal (i.p.) treatment as after i.t. treatment. In the present study, DEX showed increased whereas BUD showed decreased inhibitory capacity when given by aerosol 18-24 h before challenge. The duration of the anti-anaphylactic activity after inhalation was longer for DEX than for BUD.

Administration, Inhalation↗
PubMed1985

Importance of particulate antigen for the induction of dual bronchial reaction in guinea-pigs.

There has been a lack of small animal models for the secondary allergic response (SAR) seen after bronchial challenge in many asthmatic patients. We have found that challenge with particulate instead of soluble antigen will provoke an SAR-like bronchial obstruction in the guinea-pig. The particulate form was obtained by coupling the antigen covalently to Sepharose beads (approximately 100 microns). Different experiments suggest that SAR is obtained only when the challenge is induced via IgE-mediated mechanisms and when the antigen is sufficiently large to provoke frustrated phagocytosis by the invading inflammatory cells. As judged in lungs sections SAR was related to bronchiolitis.

Airway Resistance↗
PubMed1985

Dexamethasone reduces fat-induced release of neurotensin in the rat.

The effect of glucocorticoids on the release of neurotensin (NT) was studied in the rat. Oleic acid (200 microliters) was instilled into the duodenum of fasted rats given saline or 1 mg . kg-1 dexamethasone subcutaneously 16 h prior to the experiment. Neurotensin-like immunoreactivity (p-NTLI) was analysed in unextracted plasma with the C-terminal directed NT antiserum 6-8206. Pretreatment with dexamethasone almost totally abolished the fat-induced increase in p-NTLI. The data suggest that glucocorticoids may modulate the post-prandial release of NT. Since NT is known to constrict the vascular beds of subcutaneous adipose tissue, this effect of glucocorticoids may be one of the factors responsible for the abnormal distribution of fat caused by high levels of glucocorticoids, e.g. in Cushing's syndrome.

Animals↗
PubMed1984

Inhibitory effect of glucocorticosteroids on anti-IgE-induced histamine release from human basophilic leukocytes: evidence for a dual mechanism of action.

Anti-IgE-induced histamine release from human leukocytes is inhibited when the cells before challenge are cultured overnight in the presence of glucocorticoids (GCSs). The present report suggests that the GCSs might exert their effect by at least a dual mechanism of action. Histamine release was induced by a suboptimum concentration of anti-IgE. When the release recorded in the presence of the steroid is plotted against the release recorded in its absence, the data points of several experiments fit a regression line characterized by two parameters: its slope and its intercept with the abscissa. Structure-activity examination with selected GCSs indicates that the orders of potency for affecting these two parameters are not identical. Furthermore, pulse experiments suggest that the cells require different times of contact with the steroid to express inhibition according to the two parameters. The removal of adherent cells or platelets did not markedly affect the degree of leukocyte histamine release or its inhibition by a given GCS, suggesting that the steroid interacts directly with the basophil. Finally, steroid-induced inhibition was not affected by the putative phospholipase A2-inhibitor p-bromophenacylbromide (BPB) or the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA).

Antibodies, Anti-Idiotypic↗
PubMed1984

Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16 alpha, 17 alpha-acetal-substituted glucocorticoids.

The affinity for the glucocorticoid receptor in rat skeletal muscle of some glucocorticoids with a new type of 16 alpha, 17 alpha-acetal substituent has been estimated and correlated to the glucocorticoid activities in three in vivo systems in rats. Budesonide (an approximately 1:1 mixture of the C(22) epimers of 11 beta, 21-dihydroxy-16 alpha, 17 alpha-[(22R,S)-propylmethylenedioxy]-pregna-1,4-diene-3,20-dione) and the isolated (22R)- and (22S)-epimers bound to the same binding site as the potent glucocorticoids dexamethasone (DEX) or triamcinolone 16 alpha, 17 alpha-acetonide (TA), but with even higher affinity than DEX or TA, despite the lack of a 9 alpha-fluoro atom in budesonide and its epimers. The (22R)-epimer was twice as active as the (22S)-epimer, 4 times more active than TA, and 14 times more active than DEX. The introduction of a 9 alpha-fluoro atom slightly decreased the binding affinity of the (22R)-epimer of budesonide, in contrast to the positive effect of 9 alpha-fluorination of, e.g., 16 alpha, 17 alpha-acetonides. The negative influence of 9 alpha-fluorination of the (22R)-epimer was partially reversed in the 6 alpha, 9 alpha-difluorinated (22R)-epimer. Nevertheless, the fluorinated compounds were more active than DEX and TA (8 and 11 times more active than DEX, and 2 and 3 times more active than TA, in case of the 9 alpha-fluoro- and 6 alpha, 9 alpha-difluoro-derivatives of the (22R)-epimer, respectively). Budesonide is metabolized mainly to 16 alpha-hydroxyprednisolone (11 beta, 16 alpha, 17 alpha, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione) and 6 beta-hydroxy-budesonide. Both metabolites were very weak competitors for the ligand-binding sites on the receptor (3% and 6% of the affinity of DEX, respectively). The affinity for the receptor in vitro was closely correlated to the topical glucocorticoid activity in vivo for the 12 steroids compared (r = 0.98; R = 0.98), which supports the contention that in vitro tests for receptor affinity are useful when screening for agonists among steroids with the present type of structures. The results on receptor-ligand interaction are in accordance with X-ray crystallographic data available for some steroids.

Animals↗
PubMed1982

Topical and systemic glucocorticoid potencies of budesonide and beclomethasone dipropionate in man.

Topical anti-inflammatory (cutaneous "vasoconstriction") and systemic glucocorticoid (depression of plasma cortisol and changes in differential WBC count) potencies of the two glucocorticoids budesonide and beclomethasone dipropionate (BDP) were compared in human volunteers. After topical application, budesonide was 2-3 times more potent than BDP in inducing "vasoconstriction". After oral administration, on the other hand, budesonide was 2-4 times less potent than BDP in depressing plasma cortisol and changing the total or differential WBC. After inhalation, too, significant differences in favour of budesonide were noted, but the divergence between the drugs was less pronounced. The improved relationship between the topical and systemic glucocorticoid effects of budesonide makes it a promising alternative for aerosol treatment in asthma.

Administration, Oral↗
PubMed1982

Influence of 16 alpha, 17 alpha-acetal substitution and steroid nucleus fluorination on the topical to systemic activity ratio of glucocorticoids.

The use of topical glucocorticosteroid therapy on large skin areas or in the lung is sometimes restricted by the occurrence of unwanted, general corticoid actions owing to a profound systemic absorption. To decrease this risk potent glucocorticoids with an enhanced ratio between their topical and their systemic glucocorticoid potencies are wanted. Therefore, structure-activity studies were performed in rat models to investigate what influences the type of substitution in the 16 alpha, 17 alpha-acetal group and the introduction of fluorine in the 9 alpha- or the 6 alpha, 9 alpha-positions have on the topical and the systemic activities, respectively. The introduction of an unsymmetrical 16 alpha, 17 alpha-acetal group (named acetal type B) markedly enhanced the topical anti-inflammatory potency compared with that of the conventional 16 alpha, 17 alpha-acetonide group (named acetal type A). Both acetal types had a similar systemic glucocorticoid potency, however, 9 alpha-Fluoro and especially 6 alpha, 9 alpha-difluoro substitution, on the other hand, enhanced the systemic glucocorticoid activity more than they raised the topical anti-inflammatory potency. Optimal topical to systemic activity ratio was obtained with a nonhalogenated corticoid of acetal type B structure. This compound, budesonide, had at least the same high topical anti-inflammatory potency as fluocinolone acetonide but was about 10 times less potent than this reference to induce systemic glucocorticoid actions. Its lower systemic activity is probably due to a more rapid biotransformation in the liver.

Acetals↗
PubMed1982

Biotransformation rate (in vitro) and systemic potency (in vivo) of the topical glucocorticoid budesonide in male and female rats.

Budesonide is a glucocorticoid of clinical interest for the topical treatment of skin and respiratory diseases. The in vitro liver biotransformation rate and in vivo systemic potency (thymus involution) of budesonide were studied in male and female rats. The biotransformation rate of [3H]-budesonide was about 4 times slower in the female than in the male rat liver 9000 g supernatant (t 1/2; 230 and 57 min, respectively). The systemic potency of budesonide after peroral or subcutaneous administration was higher (by factors of 6 and 2, respectively) in the female than in the male rat. These results suggest that the liver biotransformation rate of budesonide is of great importance in reducing its systemic action in the male rat.

Animals↗