Three distinct anti-allergic drugs, amlexanox, cromolyn and tranilast, bind to S100A12 and S100A13 of the S100 protein family.
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To investigate the roles of calcium-binding proteins in degranulation, we used three anti-allergic drugs, amlexanox, cromolyn and tranilast, which inhibit IgE-mediated degranulation of mast cells, as molecular probes in affinity chromatography. All of these drugs, which have different structures but similar function, scarcely bound to calmodulin in bovine lung extract, but bound to the same kinds of calcium-binding proteins, such as the 10-kDa proteins isolated in this study, calcyphosine and annexins I-V. The 10-kDa proteins obtained on three drug-coupled resins and on phenyl-Sepharose were analysed by reversed-phase HPLC. It was found that two characteristic 10-kDa proteins, one polar and one less polar, were bound with all three drugs, although S100A2 (S100L), of the S100 family, was bound with phenyl-Sepharose. The cDNA and deduced amino acid sequence proved our major polar protein to be identical with the calcium-binding protein in bovine amniotic fluid (CAAF1, S100A12). The cDNA and deduced amino acid sequence of the less-polar protein shared 95% homology with human and mouse S100A13. In addition, it was demonstrated that the native S100A12 and recombinant S100A12 and S100A13 bind to immobilized amlexanox. On the basis of these findings, we speculate that the three anti-allergic drugs might inhibit degranulation by binding with S100A12 and S100A13. (+info)
A comparative study of the effects of ketotifen, disodium cromoglycate, and beclomethasone dipropionate on bronchial mucosa and asthma symptoms in patients with atopic asthma.
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Asthma is a chronic inflammatory disorder of the airways that is characterized by infiltration of many inflammatory cells into the bronchial mucosa. We compared the effects of ketotifen, disodium cromoglycate (DSCG), and beclomethasone dipropionate (BDP) on inflammatory cells in the bronchial mucosa and on the asthma symptoms of patients with atopic asthma. In this 12-week parallel study, 32 patients were randomly allocated to either the ketotifen group (2 mg day-1, n = 13), DSCG group (8 mg day-1, n = 9) or BDP (400 micrograms day-1, n = 10). Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Before and after treatment, pulmonary function and bronchial responsiveness to methacholine were evaluated, and fibreoptic bronchoscopy and biopsy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. We performed immunohistochemistry using specific monoclonal antibodies for activated eosinophils (EG2), mast cells (AA1), and T cells (CD3, CD4, and CD8). Our clinical findings showed significant improvement in symptom score and bronchial responsiveness (P < 0.01) each) in all groups. Both the DSCG and the BDP groups had significantly better symptom scores than the ketotifen group (P < 0.05, both groups). PEF significantly increased in the DSCG group in comparison to the ketotifen (P < 0.01) and BDP (P < 0.05) groups, FEV1% increased significantly in the DSCG (P < 0.01) and BDP (P < 0.05) groups in comparison to the ketotifen group. Compared with their baseline values, treatment significantly decreased EG2+ activated eosinophils, and CD3+ and CD4+ T cells, in each group (P < 0.01). Both the DSCG (P < 0.05) and the BDP groups (P < 0.01) exhibited significant decreases in AA1+ mast cell count, but this was not observed in the ketotifen group. Comparing before- and after-treatment values, only the DSCG group exhibited a significant decrease in the number of CD8+ T cells (P < 0.01). Ketotifen, DSCG, and BDP all showed anti-inflammatory activity as determined by examination of the bronchial mucosa of asthmatic patients; and both the DSCG and BDP groups had better clinical responses than the ketotifen group. (+info)
Clinical trial experience by simulation: a workshop report.
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A new computer program for experimental design simulation was used in a three-day postgraduate workshop on clinical trials. Participants were given information on a fictitious new drug and asked to design a trial to evaluate it. On the first day they reviewed the data and designed a protocol, and results for these specifications were generated on the computer. The second day was spent analysing results, and on the last day the findings of the different studies were presented at a symposium. Flexibility of the program ensured a high degree of realism in all trials and emphasised the influence of design on results and conclusions. (+info)
Inhibitory effects of Sasa senanensis Rehder extract (SE) on calcium-ionophore A23187-induced histamine release from rat peritoneal exudate cells.
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The effects of Sasa senanensis Rehder extract (SE) by alkaline hydrolysis on histamine release from rat peritoneal exudate cells (PECs) were examined. Preincubation with SE for 5 min suppressed calcium-ionophore A23187-induced histamine release in a concentration-dependent manner. A23187 evoked a quick increase in cytoplasmic free calcium ([Ca2+]i) levels in the presence of extracellular calcium. Preincubation with SE also had an inhibitory effect on calcium influx increases induced by A23187. These results indicate that SE prevents degranulation from rat PECs by inhibiting [Ca2+]i level elevation. (+info)
Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion.
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AIMS: To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method. RESULTS: No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) microg, 10.4 (10.9) microg and 83.7 (71.1) microg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) microg, 61.2 (28.3) microg and 305.6 (82.3) microg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) microg, 49.3 (18.1) microg and 184.9 (98.4) microg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h. CONCLUSIONS: The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques. (+info)
Plasma concentrations of disodium cromoglycate after various inhalation methods in healthy subjects.
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AIMS: To compare the plasma concentrations of disodium cromoglycate (DSCG) following various inhalation procedures in healthy volunteers. METHODS: Nine healthy subjects inhaled 2 mg of aerosol, 20 mg of nebuliser solution only, 20 mg of nebuliser solution mixed with isotonic saline, or 20 mg of nebuliser solution mixed with saline and procaterol, a beta2-adenoceptor agonist, on separate occasions 2-3 weeks apart. Plasma concentrations of DSCG were determined by high-performance liquid chromatography (h.p.l.c.). RESULTS: The peak plasma concentrations of DSCG were 1.5+/-0.7 (range 0.4-2.4) ng ml-1 in the aerosol group, 8.8+/-6.2 (range 5.3-19.9) ng ml-1 in the nebuliser solution only group, 17.2+/-16.3 (range 5.0-38.6) ng ml-1 in the nebuliser solution plus isotonic saline group, and 24.5+/-11. 9 (range 10.2-44.9) ng ml-1 in the nebuliser solution plus saline and procaterol group. Thus subjects who used the nebuliser had markedly higher plasma concentrations of DSCG than subjects who used the aerosol inhaler. CONCLUSIONS: These findings may have important implications for the evaluation of inhalation treatment with DSCG for bronchial asthma. (+info)
Expression of adhesion molecules and effect of disodium cromoglycate treatment in asthmatics.
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Allergic processes are complex disorders in which inflammatory and immunological mechanisms are involved. Many studies indicate that the adhesion molecules are upregulated in allergic inflammation, and play a critical role in the pathogenesis of allergic inflammation. Modulation of the expression of adhesion molecules may provide a potential new target for therapeutic intervention in allergic diseases. In the present study the changes expression of adhesion molecules CD11a, CD18 (LFA-1), CD54 (ICAM-1) and L-selectin (CD62L) and VLA-4 (CD49d) were analysed by flow cytometry. Serum concentrations of soluble ICAM-1, VCAM-1 and soluble low affinity receptor for IgE concentrations sCD23 were measured by ELISA in atopic patients with mild asthma before and after treatment by disodium cromoglycate (DSCG). The most significant finding was a significant decrease of ICAM-1 expression on monocytes and CD49d on monocytes and lymphocytes as well as an increase of L-selectin expression on monocytes after treatment with DSCG, without any associated effect on CD11a and CD18. The levels of soluble ICAM-1 and VCAM-1 were not changed, only the levels of soluble CD23 that plays a regulatory role in ongoing IgE production, were decreased in asthmatic patients after the treatment with DSCG. These results suggest that DSCG diminishes cell activation. (+info)
Effect of disodium cromoglycate treatment on peripheral blood mononuclear cell adhesion to cultured endothelium in allergic asthmatics.
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In this study we have compared the adhesion of peripheral blood mononuclear cells (PBMC) to human umbilical vein endothelial cells (HUVEC) in a healthy control group with two groups of allergic asthmatics, not treated or treated with disodium cromoglycate (DSCG). The adhesion and blocking experiments were performed by the flow cytometric adhesion assay. No differences in the adhesion of lymphocytes were observed in any of the groups. The monocytes obtained from DSCG non-treated patients have shown significant (P < 0.05) enhancement of adhesion to HUVEC in comparison to healthy controls. The treatment of asthmatic patients with DSCG downregulated the monocyte adhesion to cultured endothelial cells (ECs) and this was comparable to the group of normal donors. The DSCG may have a therapeutic effect on the regulation of monocyte adhesion in inflammatory and allergic diseases. The binding ability of untreated asthmatic PBMC to cultured ECs was partially inhibited by monoclonal antibody anti-CD54, suggesting that the increased EC adhesiveness for monocytes from allergic asthmatics may be at least partially dependent on the ICAM-1 adhesion pathways. Our results also indicate that the blocking agent anti-CD18 was not essential for monocyte-endothelial interactions in allergic asthma. (+info)