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1.
Osteoporos Int ; 20(9): 1595-601, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19145396

ABSTRACT

UNLABELLED: Bone turnover markers such as serum C-terminal cross-linking telopeptide of type I collagen (CTX-I) can be used to assess drug efficacy in osteoporosis. This study evaluated the pattern of CTX-I suppression in postmenopausal osteoporotic women receiving ibandronate. Ibandronate decreased serum CTX-I levels within 3 days of therapy initiation. Over 6 months, the levels remained suppressed below baseline. INTRODUCTION: This randomized, double-blind, placebo-controlled study evaluated the rapidity of onset and pattern of suppression of the bone resorption marker serum CTX-I in women with postmenopausal osteoporosis (PMO) who received once-monthly oral ibandronate. METHODS: Women diagnosed with PMO received once-monthly oral ibandronate (150 mg) or placebo for 6 months. Serum CTX-I was measured at baseline and after study dose administration on day 3 (month 1 only) and days 7, 14, 21, and 28 (months 1-6). Bone-specific alkaline phosphatase was measured on days 7 and 28 (months 1-6). RESULTS: This study enrolled 67 women: 49 received ibandronate, 17 received placebo, and one took no study drug. At day 3, median reduction in serum CTX-I from baseline was 70.2% with ibandronate and 6.0% with placebo (difference, -64.2%; 95% confidence interval, -80.3% to -46.2%; p < 0.0001). In women receiving ibandronate, serum CTX-I levels remained consistently below baseline, exhibiting a regular monthly fluctuating pattern of suppression over 6 months. Ibandronate was well-tolerated. CONCLUSIONS: Monthly ibandronate decreased serum CTX-I within 3 days. Over 6 months, in women receiving once-monthly ibandronate, serum CTX-I remained suppressed below baseline. A monthly fluctuation, related to time from last dose, was observed.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Bone Remodeling/drug effects , Bone Resorption/drug therapy , Collagen Type I/blood , Diphosphonates/therapeutic use , Osteoporosis, Postmenopausal/drug therapy , Peptides/blood , Bone Resorption/blood , Bone Resorption/prevention & control , Double-Blind Method , Drug Administration Schedule , Female , Humans , Ibandronic Acid , Middle Aged , Osteoporosis, Postmenopausal/blood , Prospective Studies , Treatment Outcome
2.
Int Arch Allergy Immunol ; 128(1): 51-8, 2002 May.
Article in English | MEDLINE | ID: mdl-12037401

ABSTRACT

BACKGROUND: Besides being highly effective in the treatment of allergic and nonallergic rhinitis with eosinophilia, intranasal corticosteroids appear to be useful in reducing nasal polypoid lesions and the likelihood of polyp recurrence after surgery. We evaluated the ability of fluticasone propionate to downregulate fibroblast functions related to nasal inflammation and remodeling. METHODS: Primary nasal polyp tissue-derived fibroblasts were stimulated with tumor necrosis factor (TNF)-alpha or interleukin (IL)-4 or basic fibroblast growth factor (bFGF) in the presence of fluticasone propionate (0.1-100 nM). Fibroblast proliferation, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression and eotaxin release were then evaluated. RESULTS: As compared with unstimulated cultures, a significant increase in fibroblast proliferation was observed when the cells were stimulated with bFGF (p < 0.05), but not with TNF-alpha or IL-4 (p > 0.05). TNF-alpha induced an upregulation of ICAM-1 expression (p < 0.05), which was not seen in fibroblasts cultured in the presence of IL-4 or bFGF. No changes in VCAM-1 expression were induced by TNF-alpha, IL-4 or bFGF, whereas both TNF-alpha and IL-4 increased eotaxin release (p < 0.05). Both bFGF-induced fibroblast proliferation and TNF-alpha-induced ICAM-1 expression were significantly reduced by fluticasone, starting at the dose of 1 and 10 nM, respectively (p < 0.05). Fluticasone at concentrations of 1-100 nM effectively inhibited eotaxin release by TNF-alpha- or IL-4-stimulated fibroblasts (p < 0.05). CONCLUSIONS: The pharmacologic activity of fluticasone in patients with chronic upper airway inflammatory disease may include inhibition of resident fibroblast functions involved in airway inflammation and remodeling.


Subject(s)
Androstadienes/pharmacology , Anti-Inflammatory Agents/pharmacology , Nasal Polyps/immunology , Administration, Topical , Adult , Cell Division/drug effects , Chemokine CCL11 , Chemokines, CC/analysis , Chemokines, CC/biosynthesis , Down-Regulation/drug effects , Enzyme-Linked Immunosorbent Assay , Female , Fibroblast Growth Factor 2/immunology , Fibroblast Growth Factor 2/pharmacology , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/immunology , Flow Cytometry , Fluticasone , Glucocorticoids , Humans , Intercellular Adhesion Molecule-1/analysis , Intercellular Adhesion Molecule-1/biosynthesis , Interleukin-4/immunology , Interleukin-4/pharmacology , Male , Nasal Polyps/drug therapy , Nasal Polyps/pathology , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/pharmacology , Vascular Cell Adhesion Molecule-1/analysis , Vascular Cell Adhesion Molecule-1/biosynthesis
3.
J Immunol ; 167(9): 5329-37, 2001 Nov 01.
Article in English | MEDLINE | ID: mdl-11673549

ABSTRACT

Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early participants in inflammatory responses as well as potential targets for anti-inflammatory drugs. In this study, we show that fluticasone propionate (FP), a powerful inhaled corticosteroid (ICS), displays novel anti-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by IL-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kinase). Contrarily, in mildly or fully differentiated myofibroblastic cultures, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitutive and TGF-beta-induced expression of alpha-smooth muscle actin, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. Finally, FP displays an additional powerful anti-inflammatory effect, decreasing nuclear translocation of NF-kappaB independent of the degree of myofibroblastic differentiation. These data 1) suggest that myofibroblasts are priority targets for ICS, which is able to revert them to a normal phenotype even if they appear to be already engaged in their differentiation, and 2) may help to explain why asthma is improved by an early ICS treatment, whereas advanced asthma is more resistant to these drugs.


Subject(s)
Androstadienes/pharmacology , Anti-Inflammatory Agents/pharmacology , Lung/drug effects , Protein-Tyrosine Kinases , Actins/analysis , Administration, Inhalation , Adult , Androstadienes/administration & dosage , Cell Differentiation , Cells, Cultured , DNA-Binding Proteins/physiology , Fibroblasts/drug effects , Fibroblasts/physiology , Fluticasone , Humans , Interleukin-13/pharmacology , Interleukin-4/pharmacology , Lung/cytology , Microscopy, Confocal , NF-kappa B/metabolism , Proteins/physiology , Reverse Transcriptase Polymerase Chain Reaction , STAT3 Transcription Factor , TYK2 Kinase , Trans-Activators/physiology
4.
Eur Respir J ; 18(1): 139-45, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11510784

ABSTRACT

Beta2-adrenoreceptor agonists have pharmacological properties that may suggest an inhibitory effect on various aspects of the inflammatory and repair processes that characterize asthma. Since fibroblasts express beta2-adrenoreceptors, the effects of different concentrations (0.1-100 nM) of fluticasone propionate (FP), salmeterol (S) and their combination (FP+S) on lung fibroblast proliferation and adhesion molecule expression were evaluated. Stimulation of human foetal lung fibroblasts with a fibrogenic cytokine, basic fibroblast growth factor (bFGF), resulted in a [methyl-3H] thymidine ([3H]TdR) uptake, four-fold higher than that of control cultures (p=0.0001) and was significantly inhibited by S, at all the concentrations tested (0.1-100 nM; p<0.05). No changes in bFGF-induced cell proliferation were observed in the presence of FP (0.1-100 nM; p>0.05, all comparisons). In addition, the association FP+S did not improve the inhibitory activity of S alone (p>0.05, each comparison). An upregulation of intercellular adhesion molecule-1 (ICAM-1) expression was induced by tumour necrosis factor-alpha (TNF-alpha) (p=0.0004), but not by interleukin-4 (IL-4) (p>0.05), while none of the two cytokines were able to increase hyaluronic-cellular adhesion molecule (H-CAM) expression by lung fibroblasts (p>0.05). A significant downregulation of ICAM-1 or H-CAM expression was demonstrated in the presence of FP or S, at all concentrations tested (0.1-100 nM; p<0.01, each comparison). Interestingly, S (10 nM and 100 nM) was able to enhance the inhibitory activity of FP on ICAM-1 expression (p<0.01), but not on H-CAM expression (p>0.1). These results show that in human foetal lung fibroblasts, fluticasone propionate and salmeterol are effective in modulating in vitro, different lung fibroblast biological functions that are likely to be involved in airway remodelling.


Subject(s)
Albuterol/analogs & derivatives , Albuterol/pharmacology , Androstadienes/pharmacology , Cell Adhesion Molecules/metabolism , Cell Division/drug effects , Hyaluronic Acid/metabolism , Intercellular Adhesion Molecule-1/metabolism , Lung/cytology , Cell Line , Cytokines/pharmacology , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Fetus , Fibroblast Growth Factor 2/pharmacology , Fluticasone , Humans , In Vitro Techniques , Salmeterol Xinafoate
5.
Eur J Immunol ; 29(9): 2957-67, 1999 09.
Article in English | MEDLINE | ID: mdl-10508270

ABSTRACT

CD23-deficient and anti-CD23 monoclonal antibody-treated mice were used to investigate the role of the low-affinity receptor for IgE (CD23) in allergic airway inflammation and airway hyperresponsiveness (AHR). While there were no significant differences in ovalbumin (OVA)-specific IgE titers and tissue eosinophilia, evaluation of lung function demonstrated that CD23-/- mice showed an increased AHR to methacholine (MCh) when compared to wild-type mice but were completely resistant to the OVA challenge. Anti-CD23 Fab fragment treatment of wild-type mice did not affect the MCh-induced AHR but significantly reduced the OVA-induced airway constriction. These results imply a novel role for CD23 in lung inflammation and suggest that anti-CD23 Fab fragment treatment may be of therapeutic use in allergic asthma.


Subject(s)
Allergens/immunology , Asthma/immunology , Bronchoconstriction/immunology , Receptors, IgE/physiology , Animals , Bronchoconstrictor Agents/pharmacology , Disease Models, Animal , Eosinophils/metabolism , Female , Immunoglobulin E/biosynthesis , Macrophages, Alveolar/metabolism , Methacholine Chloride/pharmacology , Mice , Mice, Congenic , Mice, Inbred BALB C , Mice, Inbred C57BL , Ovalbumin/immunology , Ovalbumin/metabolism , Receptors, Fc/metabolism , Receptors, IgE/deficiency , Receptors, IgE/metabolism , Time Factors
6.
Clin Exp Immunol ; 115(2): 329-34, 1999 Feb.
Article in English | MEDLINE | ID: mdl-9933461

ABSTRACT

Hantaviruses cause an important human illness, HFRS. Blood samples from 22 HFRS-positive, six seronegative patients and 15 healthy controls were examined in 1995, during the largest HFRS epidemic in Croatia. Results of double- and triple-colour immunofluorescence analysis showed an increased percentage of cytotoxic T cells (CD3+CD8+) in seropositive patients compared with seronegatives and healthy controls. The majority of seropositive HFRS patients expressed activation and memory antigens on T and B lymphocytes. The percentage of CD23+ and CD21+ B lymphocytes was lower in seropositive patients. HFRS patients had elevated levels of sCD23 and five had elevated total IgE. The increased expression of both early and late T cell activation antigens, e.g. CD25, CD71 and HLA-DR, memory cells and sCD23 positively correlated with biochemical parameters (AST, ALT, urea, alpha2-globulin) during the acute phase of HFRS. The phenotypic changes observed, especially early and late T cell activation markers, as well as memory cells, could be useful parameters in the evaluation of HFRS course, and prognostic factors of HFRS severity. Additional attention should be paid to liver involvement in the pathogenesis of HFRS.


Subject(s)
Hemorrhagic Fever with Renal Syndrome/immunology , Lymphocytes/immunology , Adult , Antigens, CD/isolation & purification , Antigens, Differentiation, B-Lymphocyte/isolation & purification , B-Lymphocytes/immunology , CD3 Complex/isolation & purification , CD8 Antigens/isolation & purification , Croatia/epidemiology , Disease Outbreaks , Flow Cytometry , HLA-DR Antigens/isolation & purification , Hemorrhagic Fever with Renal Syndrome/epidemiology , Hemorrhagic Fever with Renal Syndrome/etiology , Humans , Immunoglobulin E/blood , Immunologic Memory , Liver/enzymology , Male , Phenotype , Receptors, Complement 3d/isolation & purification , Receptors, IgE/blood , Receptors, Transferrin , T-Lymphocytes, Cytotoxic , Transaminases/analysis
7.
Am J Hematol ; 59(2): 143-8, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9766799

ABSTRACT

Use of a nonlinear prediction method, such as machine learning, is a valuable choice in predicting progression rate of disease when applied to the highly variable and correlated biological data such as those in patients with chronic lymphocytic leukemia (CLL). In this work, decision-tree approach to cell phenotype-based prognosis of CLL was adopted. The panel of 33 (32 different phenotypic features and serum concentration of sCD23) parameters was simultaneously presented to the C4.5 decision tree which extracted the most informative of them and subsequently performed classification of CLL patients against the modified Rai staging system. It has been shown that substantial correlation between the percentage of expression of the CD23 molecule on CD19+ B-cells, the level of sCD23, the percentage of CD45RA+, and the absolute number of CD4CD45RA+RO+ T-cells and the clinical stages, exists. The prediction vector, composed of their concatenated values, was able to correctly associate 83% of the cases in the low-risk group (Rai stage 0), 100% of the cases in the intermediate-risk group (Rai stage I and II), and 89% of the cases in the high-risk group (Rai stage III and IV) of CLL patients. Predictivity of this vector was 100%, 95%, and 89%, respectively. In conclusion, from the described analysis, it may be inferred that two processes play important roles in the progression rate of CLL: 1.deregulated function of the CD23 gene in B-cells accompanied by the appearance of its cleaved product sCD23 in the sera; and 2. functionally impaired and imbalanced CD4 T-cell subpopulations found in the peripheral blood of CLL patients.


Subject(s)
Decision Trees , Immunophenotyping , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Aged , Aged, 80 and over , Antigens, CD/analysis , Decision Making, Computer-Assisted , Female , Humans , Lymphocytes/immunology , Male , Middle Aged , Neoplasm Staging , Predictive Value of Tests , Prognosis , Receptors, IgE/blood
8.
Leuk Lymphoma ; 25(3-4): 301-11, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9168440

ABSTRACT

Whole-blood three-color immunofluorescence analysis was used to investigate the role of CD5/CD72 and CD21/CD23 receptor-ligand pair formation on B-chronic lymphocytic leukemia (B-CLL) cells as well as sCD23 and bcl-2 oncoprotein expression in disease progression and activity and total tumor mass in B-cell chronic leukemia (B-CLL) patients. Thirty-four patients with B-CLL and 19 controls were included in the study. The majority of B-cells in B-CLL patients coexpressed CD5 and CD72 as well as the CD23 antigen. Unlike B-cells in B-CLL patients, B-cells in all healthy controls tested had high expression of CD21 antigen. We identified two groups of B-CLL patients according to high (n = 20) or low levels (n = 14) of CD21 expression on CD19+CD23+ B-cells. Only in the patients with high CD21 expression, were sCD23 levels positively correlated with factors known to have prognostic significance in B-CLL (Rai stage and TTM) and could, therefore, be used as a prognostic parameter for these B-CLL patients. Bcl-2 oncoprotein expression did not differ between these patient groups. We presumed that in patients with a lower expression of CD21 antigen, the contribution of the CD21 molecule to homotypic adhesion was lacking. Further studies are necessary to determine the possible association of higher expression of the CD21 antigen with disease progression and the aggressive character of the B-CLL.


Subject(s)
Antigens, CD/metabolism , B-Lymphocytes/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Aged , Antigens, Differentiation, B-Lymphocyte/metabolism , B-Lymphocytes/immunology , CD5 Antigens/metabolism , Case-Control Studies , Female , Flow Cytometry , Fluorescent Antibody Technique, Direct/methods , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Neoplasm Staging , Phenotype , Receptors, Complement 3d/metabolism , Receptors, IgE/blood , Receptors, IgE/metabolism
10.
Anticancer Res ; 15(5B): 1883-8, 1995.
Article in English | MEDLINE | ID: mdl-8572573

ABSTRACT

The oral administration of 100 mg/Kg/day of hen egg-white lysozyme (Lysozyme) for 8 consecutive days to mice bearing advanced MCa mammary carcinomas and treated with 5-fluorouracil (5-FU) increases the efficacy of 5-FU on primary tumor growth and on lung metastasis formation and particularly on the postsurgical survival time. These effects are accompanied by the correction of the reduced in vitro response to ConA of lymphocytes obtained from the spleen of the treated mice. In vitro, lysozyme is capable of inducing proliferative activity in a population of blast cells, obtained by a mixed population of mononuclear cells harvested from the spleen of healthy mice, and of evoking a marked proliferative effect to IL-2 in a condition in which, in lysozyme untreated lymphocytes, IL-2 is completely uneffective. These data stress the effects of lysozyme on host immunity following oral administration and moreover indicate the beneficial role of this peptide in conditions in which the increase of host responses can significantly contribute to the success of the treatment.


Subject(s)
Antineoplastic Agents/therapeutic use , Concanavalin A/pharmacology , Fluorouracil/therapeutic use , Interleukin-2/pharmacology , Lymphocyte Activation/drug effects , Muramidase/pharmacology , Neoplasms, Experimental/drug therapy , Animals , Drug Synergism , Female , Mice , Mice, Inbred CBA , Neoplasms, Experimental/immunology
11.
Int J Oncol ; 5(2): 275-84, 1994 Aug.
Article in English | MEDLINE | ID: mdl-21559586

ABSTRACT

A new biological response modifier, L-(adamant-2-yl)glycyl-L-alanyl-D-isoglutamine hydrochloride (AdTP), recently synthesized and characterized for antitumor, antiviral and immunomodulating properties was studied in comparison to the peptidoglycan monomer (PGM) isolated from Brevibacterium divaricatum to test the effects of their use concomitant to that of anticancer cytotoxic drugs such as cyclophosphamide, 5-fluorouracil (5-FU), cisplatin and 4-(3,3-dimethyl-1-triazeno)-5-carboxamide (dacarbazine). The experiments, performed using both Lewis lung carcinoma and MCa mammary carcinoma of CBA mouse, indicated that: a) the cytotoxic drugs, used at the maximum tolerated doses, caused different degrees of reduction of the tumors; b) the same drugs reduced lung metastases with greater efficacy when treatments were applied at the early stages of metastasis formation; c) AdTP, similarly to PGM confirmed its ability to increase some immunological parameters of lymphocytes obtained from the spleens of the treated mice; d) AdTP increased the effects of 5-FU on lung metastases but failed to show any increase of life expectancy with any treatment performed. These data indicate that AdTP, although increasing some functional responses of lymphocytes in vitro, does not improve the therapeutic activity of cyclophosphamide, cisplatin, 5-FU and dacarbazine in the experimental models presently used.

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