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J Jozefonvicz

Publications and source records attributed to J Jozefonvicz.

85 records · Page 5Linked to original sources
PubMed1985

Anticoagulant activity of dextran derivatives. Part II: Mechanism of thrombin inactivation.

The mechanism of anticoagulant activity of dextrans substituted with carboxylic and benzylamide sulphonate groups is studied by various coagulation tests. These derivatives exhibit a heparin-like antithrombic activity which requires the presence of antithrombin III; however they are less effective than heparin on a weight basis. They also exert a direct antithrombic activity by an antithrombic III independent pathway; but this action is negligible compared to the thrombin inhibition observed in the presence of antithrombin III. Dextran derivatives have been prepared with antithrombic properties similar to those of heparin.

Antithrombin III↗
PubMed1985

Anticomplementary activity of dextran derivatives.

Substitution with carboxylic and benzylamine sulphonated groups conferred on dextran both antithrombic activity and the capacity to inhibit formation of the amplification C3 convertase of complement. In dextrans substituted with carboxylic groups (greater than 40%), a high content of sulphonate (greater than 10%) resulted in both anticomplementary and antithrombic properties whereas a lower content of sulphonate resulted in high anticomplementary but weak antithrombic activity. The anticomplementary activity of highly substituted dextrans was similar to that of heparin, although anticoagulant activity was much lower than in heparin, confirming independent structural requirements for both activities in the heparin molecule.

Complement C3-C5 Convertases↗
PubMed1984

High-pressure size-exclusion chromatography of anticoagulant materials.

A comparative determination of molecular weights of anticoagulant materials is made on different types of high-performance liquid chromatographic stationary phases in aqueous media. The influence of different elution parameters is reported. Narrow-molecular-weight-distribution polystyrenesulphonates are used as standards for the calibration curves. Slight retentions are observed on unmodified silica supports. The commercially available grafted silica columns give similar results for the molecular weight values of heparin. A retention of pentosan polysulphate is observed on a TSK column. However, the size of this anticoagulant polymer is determined on the other grafted silica columns.

Anticoagulants↗
PubMed1984

Antithrombic properties of insoluble modified polystyrene: Part I.

Chlorosulfonated polystyrenes grafted with arginyl methyl ester have been synthetized and characterized by elemental analyses. When suspended in plasma or in fibrinogen solutions, these insoluble polymers cause an increase in the thrombin clotting time. Consequently the antithrombin activity observed is not dependent upon to the presence of antithrombin III. Binding between the resin and thrombin can be demonstrated. An approximative value of the affinity constant is calculated: 2.3 X 10(6) 1/M. At high ionic strength, thrombin can be desorbed and exhibits normal coagulation properties. The prolongation of the thrombin time therefore can be attributed to the thrombin-resin interaction.

Absorption↗
PubMed1984

Anticoagulant activity of dextran derivatives. Part I: Synthesis and characterization.

Substituted dextrans bearing carboxymethyl and benzylsulphonate groups have been prepared. These materials exhibit an antithrombic activity correlated with the ratio of each substituent. The highest activity is obtained when the dextran derivative contains more than 50% of carboxylic acid groups and simultaneously about 15% of benzylsulphonate functions.

Anticoagulants↗
PubMed1982

Antithrombic activity of some polysaccharide resins.

Crosslinked dextrans (Sephadex) bearing essentially carboxymethyl, benzylsulphonate and alpha-amino acid groups have been synthesized. The antithrombic activity of the resins may be the result of a cooperative effect between the functional groups. The binding of benzylsulphonate to carboxymethylated Sephadex endows these materials with activity. However the highest activity is obtained when the resins contain simultaneously benzylsulphonate, alpha-amino acid and carboxylic acid groups.

Anticoagulants↗
PubMedDate not supplied

Affinity of human anti-factor VIII antibodies for functional polystyrene supports.

Human anti-factor VIII antibodies (anti-FVIII) neutralize Factor VIII (FVIII) procoagulant activity. These antibodies appear in about 5-15 per cent of severely affected patients with haemophilia A treated with FVIII concentrates (Mannucci, 1993). In order to obtain non-thrombogenic materials able to interact specifically with anti-FVIII, amino acids residues that mimic part of the FVIII molecule recognized by anti-FVIII have been grafted. Several cross-linked polystyrenes were functionalized with sulphonate and tyrosine sulphamide groups or tyrosine derivatives sulphamide groups such as methyl ester tyrosine, or the peptides aspartic acid methyl amide tyrosine, tyrosine aspatic acid methyl amide or aspartic acid aspatic acid methyl amide tyrosine. The in vitro removal of anti-FVIII from haemophilic A plasma was performed on different supports. These polymers exhibit strong and selective affinity for the anti-FVIII. The amount of adsorbed anti-FVIII varies with the composition of the polymer and a maximum is achieved for 15-35 per cent of amino acid sulphamide groups. The influence of different chemical groups on the surface of the polymeric solid supports on the adsorption of anti-FVIII was also studied.

Autoantibodies↗
PubMedDate not supplied

Sulfonated dextran inhibits complement activation and complement-dependent cytotoxicity in an in vitro model of hyperacute xenograft rejection.

In the present study, we demonstrate that a substituted soluble dextran derivative bearing 73% carboxylic groups and 15% benzylamide sulfonate groups, termed CMDBS25, inhibits complement activation and complement-mediated damage in an in vitro model of xenogeneic rejection. Incubation of porcine aortic endothelial cells with normal human serum resulted in time-dependent complement consumption as assessed by C3a generation in the fluid phase and deposition of activated complement fragments C3, C5 and of C5b-9 on target cells. The presence of C5b-9 membrane attack complex was associated with 51Cr release from prelabelled endothelial cells. The addition of 5-25 mg of CMDBS25/ml under the experimental conditions used, inhibited complement activation and C3a generation in a dose-dependent fashion. CMDBS25 (25 mg/ml) totally suppressed iC3b, C5 and C5b-9 cytolytic complex deposition on cells and inhibits by 42% lysis of target endothelial cells. Native dextran had no effect. Our observations document the anti-complementary properties of sulfonated dextran derivatives and their potential as therapeutic agents for the prevention of complement-dependent hyperacute xenograft rejection.

Animals↗
PubMedDate not supplied

Extending insulin action in vivo by conjugation to carboxymethyl dextran.

The biochemical and pharmacological properties of bioactive peptides and proteins can be altered by conjugation with polymers. This report describes site-specific attachment of insulin to activated carboxyl groups of carboxymethyl dextran (CMD, MW=51000) through the GlyA1 insulin amino group. On average, three or four insulin molecules were grafted to a CMD linear chain. Coupled insulin molecules were properly folded, and the bioactivity of conjugated insulin in the blood glucose depression assay was 9.6 IU/mg, which was only 2.6 times less than that for native insulin. The cell growth study indicated that the CMD-insulin conjugate was as mitogenic as insulin on vascular smooth muscle cells, whereas the starting CMD polymer was not. The insulin receptor binding constant of the conjugate (3.6 x 10[9] M[-1]) compared well with that of native insulin (7.6 x 10[9] M[-1]), indicating that the CMD chain does not present any major constraints to binding. Plasma clearance of CMD-insulin obeyed a two-compartment pharmacokinetic (PK) model with a CMD-insulin conjugate plasma elimination half-life of 114.1 min, which was significantly longer than that of soluble Zn-insulin (12.4 min). In contrast, pharmacodynamic (PD) profiles (blood glucose lowering effects) after intravenous (iv) administration of the conjugate or insulin in rats were not different. Subcutaneous (sc) administration of the conjugate resulted in a significantly prolonged plasma profile with a noncompartmental PK parameter mean residence time (MRT) of 103.5 min which was significantly longer than that of soluble Zn-insulin (40.5 min). This was reflected in the protracted PD effect of sc administered conjugate with time needed to reach minimum glucose concentration Tnadir of 95.7 min, which was significantly longer than that of insulin (62 min). We conclude that the conjugation of insulin to CMD leads to a bioactive conjugate with a delayed sc PD profile showing prolonged response, resembling intermediate acting insulin preparations.

Animals↗
PubMedDate not supplied

Breast carcinoma cell uptake and biodistribution of technetium-99m-carboxymethyl benzylamide dextran.

Carboxymethyl Benzylamide Dextran (CMDB7) displayed an in vitro growth inhibitory activity on breast tumor cells. CMDB7 is able to disrupt the interaction of angiogenic growth factors (FGF2, TGF beta and PDGF) with their membrane receptors. This compound blocks the angiogenesis of MDA-MB435 carcinoma xenografted in mammary fat pad and their lung metastases in nude mice. In this work, we studied the uptake of CMDB7 labeled with 99mTc in cultured human breast cancer MCF-7 cell line and the highly tumorigenic MCF-7ras cell line (Ha-ras-transfected MCF-7 cells) and the in vivo distribution in MCF-7ras tumor-bearing mice. The 99mTc-CMDB7 are stable and the intracellular concentration is time-dependent and reaches a plateau at 180 minutes. 99mTc CMDB7 uptake is much higher in MCF-7ras cells than MCF-7 cells. Since CMDB7 is internalized and could also inhibit cell proliferation by acting at nuclear sites, we investigated the MCF-7ras nuclear localization after cell fractionation. Cell fractionation revealed a cytoplasmic and nuclear internalization of CMDB7. The tumor uptakes of 99mTc-CMDB7 were 0.34%, 0.72% and 0.62% of the administrated doses per gram of tumor tissue at 1 hour, 3 hour and 5 hours respectively after their injection. The blood clearance of 99mTc CMDB7 was very rapid and the liver, spleen and kidney uptakes were very weak. These results confirm the absence of toxicity of CMDB7 and the usefulness of CMDB7 in cancer therapy by targeting breast tumors.

Animals↗
PubMedDate not supplied

Inhibitory effects of dextran derivatives in vitro on the growth characteristics of premalignant and malignant human mammary epithelial cell lines.

The effects of two dextran derivatives (CMDBS-6 and CMDBS-12) on the growth rates of three human mammary epithelial cell lines (HBL100,HH9 and MCF7) were studied. CMDBS-6 markedly inhibited the growth of all lines, while CMDBS-12 and native dextran T40 had no effect on the growth of all lines. This inhibition was dose-dependent, reversible and inversely related to the concentration of fetal calf serum. The inhibitory effect of CMDBS-6 is cytostatic but not cytotoxic. Moreover, CMDBS-6 appears to have a stronger effect on HBL100 cells which are non-tumorigenic in nude mice. In contrast, the growth of HH9 cells, which are highly tumorigenic in nude mice, is less inhibited by CMDBS-6. Whereas CMDBS-6 inhibited the HBL100 cell anchorage, that of HH9 cells was not affected. By analysing the cell distribution in the various phases of the cell cycle, we have observed that CMDBS-6 arrested HBL100 and MCF7 cell mainly in the G0/GI phase. In contrast, HH9 cells were accumulated in the G2/M phase. When treated with CMDBS-6, human mammary cells slightly increased their granularities. These results demonstrate an antiproliferative activity of CMDBS-6 which could not be explained by an inactivation of mitogens provided by the serum but suggest that this compound could exert its cytostatic effects via a cell-specific mechanism.

Amides↗
PubMedDate not supplied

Antitumor activity of low molecular weight fucans extracted from brown seaweed Ascophyllum nodosum.

The effect of low molecular weight fucans (LMW fucans) has been examined on the proliferation of tumour cells. These LMW fucans are not active on all tumour cell lines. They are not cytotoxic and inhibit CCL39 fibroblast cells and human colon adenocarcinoma Colo320DM proliferation (85% and 50% of inhibition respectively). The active concentration of sulphated polysaccharide is about 10 micrograms/mL for CCL39 cells and 100 micrograms/mL for COLO 320 DM. This inhibitory effect is fetal calf serum concentration and cell density dependent. Furthermore, fucans are internalized into CCL39 cells within the first hours of incubation. They are distributed into the cytoplasmic compartment but not in the nucleus, and are not excreted after one week of contact. In the case of COLO 320 DM cells, the same fluorescent fucan is not internalized after one week of contact, but remains strongly fixed on the cytoplasmic membrane. This inhibitory effect is not accompanied by any modifications of the cell distribution in the various phases of the cell cycle. There are no significant differences in the antitumor effect either between the various LMW fucan or with the crude extract.

Adenocarcinoma↗