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1.
Clin Microbiol Infect ; 20(1): O50-7, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23889746

ABSTRACT

Invasive candidiasis is a life-threatening infection in patients with haematological malignancies. The objective of our study was to determine the incidence, microbiological characteristics and clinical outcome of candidaemia among hospitalized adult patients with haematological malignancies. This is a population-based, prospective, multicentre study of patients ≥ 18 years admitted to haematology and/or haematopoietic stem cell transplantation units of nine tertiary care Greek hospitals from January 2009 through to February 2012. Within this cohort, we conducted a nested case-control study to determine the risk factors for candidaemia. Stepwise logistic regression was used to identify independent predictors of 28-day mortality. Candidaemia was detected in 40 of 27,864 patients with haematological malignancies vs. 967 of 1,158,018 non-haematology patients for an incidence of 1.4 cases/1000 admissions vs. 0.83/1000 respectively (p <0.001). Candidaemia was caused predominantly (35/40, 87.5%) by non-Candida albicans species, particularly Candida parapsilosis (20/40, 50%). In vitro resistance to at least one antifungal agent was observed in 27% of Candida isolates. Twenty-one patients (53%) developed breakthrough candidaemia while receiving antifungal agents. Central venous catheters, hypogammaglobulinaemia and a high APACHE II score were independent risk factors for the development of candidaemia. Crude mortality at day 28 was greater in those with candidaemia than in control cases (18/40 (45%) vs. 9/80 (11%); p <0.0001). In conclusion, despite antifungal prophylaxis, candidaemia is a relatively frequent infection associated with high mortality caused by non-C. albicans spp., especially C. parapsilosis. Central venous catheters and hypogammaglobulinaemia are independent risk factors for candidaemia that provide potential targets for improving the outcome.


Subject(s)
Candida/classification , Candidemia/epidemiology , Candidemia/etiology , Hematologic Neoplasms/complications , Adolescent , Adult , Agammaglobulinemia/drug therapy , Aged , Aged, 80 and over , Antifungal Agents/therapeutic use , Candidemia/microbiology , Candidemia/mortality , Case-Control Studies , Central Venous Catheters/adverse effects , Female , Greece/epidemiology , Hospitalization , Humans , Logistic Models , Male , Middle Aged , Prospective Studies , Risk Factors , Young Adult
2.
Bioorg Med Chem Lett ; 11(8): 1031-5, 2001 Apr 23.
Article in English | MEDLINE | ID: mdl-11327582

ABSTRACT

In the course of our research for the low-molecular weight RGD peptide mimics, we have found that a rigid 2-acylimino-3H-thiazoline structure is suitable for the peptide backbone mimics. Introduction of amidinophenyl and beta-alanine moiety as arginine and aspartic acid side-chain surrogates to this backbone mimic resulted in a highly potent fibrinogen receptor antagonist 2-(4-amidinobenzoylimino)-3,4-dimethyl-N-(2-carboxyethyl)-3H-thiazoline-5-carboxamide (7c), namely PS-028 (Ki = 46.5 +/- 5.8 microM).


Subject(s)
Blood Platelets/metabolism , Fibrinogen/metabolism , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Thiazoles/pharmacology , Animals , Binding Sites/physiology , Cell Adhesion/drug effects , Dogs , Enzyme-Linked Immunosorbent Assay , Guinea Pigs , Humans , Inhibitory Concentration 50 , Intercellular Signaling Peptides and Proteins , Mice , Oligopeptides/chemical synthesis , Peptides/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/metabolism , Thiazoles/chemical synthesis , Thiazoles/metabolism
3.
Int Arch Allergy Immunol ; 126(4): 318-24, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11815739

ABSTRACT

BACKGROUND: CD45, receptor-type protein tyrosine phosphatases (PTPases) are essential components of signaling through both the T cell receptor and the B cell antigen receptor. However, the functional significance of CD45 in the signaling pathway through the high-affinity immunoglobulin (Ig) E receptor has not yet been established. In this study, we demonstrate that the potent CD45 inhibitor negatively regulates IgE-dependent anaphylaxis and contact hypersensitivity reactions. METHOD: We have previously found that TU-572, 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]-5-isopropoxybenzimidazole, had a potent and selective inhibitory effect against PTPase activity of CD45. Using a CD45 inhibitor, we examined in vitro and in vivo IgE-mediated responses. RESULTS: TU-572 potently inhibited histamine release from rat peritoneal mast cells and mouse systemic anaphylaxis reaction using monoclonal anti-dinitrophenyl (DNP) IgE and DNP-BSA. TU-572 also suppressed the immediate-type hypersensitivity response induced by repeated epicutaneous application of trinitrochlorobenzene in BALB/c mice. CONCLUSION: These findings revealed that the PTPase activity of CD45 played a critical role in signal transduction of IgE-mediated anaphylaxis in vitro and in vivo. PTPase inhibitors such as TU-572 are useful in the treatment of allergic diseases.


Subject(s)
Anaphylaxis/drug therapy , Benzimidazoles/pharmacology , Dermatitis, Contact/drug therapy , Enzyme Inhibitors/pharmacology , Leukocyte Common Antigens/drug effects , Protein Tyrosine Phosphatases/antagonists & inhibitors , Sulfoxides/pharmacology , Animals , Benzimidazoles/therapeutic use , Enzyme Inhibitors/therapeutic use , Female , Histamine Release , Hypersensitivity, Immediate/drug therapy , Mast Cells/immunology , Mice , Mice, Inbred BALB C , Picryl Chloride/adverse effects , Rats , Rats, Sprague-Dawley , Sulfoxides/therapeutic use
4.
Bioorg Med Chem Lett ; 10(23): 2657-60, 2000 Dec 04.
Article in English | MEDLINE | ID: mdl-11128645

ABSTRACT

The synthesis and biological activity of a series of 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]benzimidazoles are described. These compounds have potent inhibitory effects against the protein tyrosine phosphatase activity of CD45. Enzymatic analysis with several phosphatases revealed that compound 5a had high specificity for CD45 compared with serine/threonine phosphatases (PP1, PP2A), tyrosine phosphatases (LAR, PTP1B and PTP-S2) and dual phosphatase (VHR).


Subject(s)
Benzimidazoles/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Protein Tyrosine Phosphatases/antagonists & inhibitors , Sulfoxides/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Leukocyte Common Antigens/metabolism , Protein Tyrosine Phosphatases/metabolism , Structure-Activity Relationship , Sulfoxides/chemistry , Sulfoxides/pharmacology
5.
Biochim Biophys Acta ; 1213(3): 302-8, 1994 Aug 04.
Article in English | MEDLINE | ID: mdl-8049243

ABSTRACT

Biological activities of two epimeric 24-fluorinated vitamin D-2 analogs, 24-fluoro-1 alpha,25-dihydroxyvitamin D-2 [24-F-1,25-(OH)2D2] and its 24-epimer [24-epi-24-F-1,25-(OH)2D2], were studied and compared with 1 alpha,25-dihydroxyvitamin D-3 [1,25-(OH)2D3] and 1 alpha,25-dihydroxyvitamin D-2 [1,25-(OH)2D2]. 24-F-1,25-(OH)2D2 was nearly as active as 1,25-(OH)2D3 and 1,25-(OH)2D2 both in regulating calcium metabolism in vivo including bone mineral mobilization and intestinal calcium transport and in inducing differentiation of HL-60 cells. While 24-epi-24-F-1,25-(OH)2D2 showed distinct properties in these two types of the actions. Though the 24-epimer was nearly as potent as 1,25-(OH)2D3 in inducing differentiation of HL-60 cells, it showed little activity in regulating calcium metabolism in vivo. The fluorine atom introduced at the 24-position of either 1,25-(OH)2D2 or its 24-epimer had no potentiating effect. This is in sharp contrast with the cases of 24- and 26,27-multifluorinated analogs of active vitamin D-3.


Subject(s)
Ergocalciferols/chemical synthesis , Animals , Biological Transport , Bone Resorption , Calcium/blood , Calcium/metabolism , Cell Differentiation/drug effects , Ergocalciferols/metabolism , Humans , Rats , Rats, Sprague-Dawley , Stereoisomerism , Tumor Cells, Cultured
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