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Effect of intravenous iron dextran on rheumatoid synovitis.

Eleven patients with rheumatoid arthritis received a total dose infusion of iron dextran for anaemia. Two of them had anaphylactic reactions and the remaining nine an exacerbation of synovitis. Quantitative infrared thermal imaging was used to assess the extent and distribution of joint involvement resulting from this therapy. In all eight patients examined the 'thermographic index' increased in two or more joint areas, indicating an increase in inflammation. Small joints of the hands were maximally affected, though larger joints when previously inflamed also worsened. Uninflamed joints were rarely affected. The exacerbation of synovitis occurred 24-48 h after completion of the iron dextran infusion and corresponded with a saturating of the serum iron binding capacity. Levels of immune complexes were unaltered, implying normal reticuloendothelial function. In one further patient, reported to have synovial flares when challenged with oral ferrous sulphate, iron dextran was infused at a lower dosage. All previously inflamed joints in this patient worsened 12 h after the infusion was discontinued. Concomitant with this was an increase of lipid peroxidation products in synovial fluid and to a less extent serum. Iron dextran in vitro stimulated lipid peroxidation, but dextran alone had no effect. It is therefore suggested that iron dextran worsens synovial inflammation by promoting lipid peroxidation.

Adult↗

Dextran 70 in prophylaxis of thromboembolic disease after surgery: a clinically oriented randomized double-blind trial.

A randomized double-blind trial of prophylaxis of thromboembolism in surgical patients judged by clinical morbidity has been completed. Altogether 831 patients over 40 years of age who underwent elective surgery of the stomach, biliary system, or colon received either dextran 70 or normal saline before the operation. Thirteen of the 435 patients on saline and three of the 396 on dextran developed pulmonary embolism. Eight of these 16 patients died of pulmonary embolism--seven in the saline group and one in the dextran group. As detected either clinically or by 125I-fibrinogen scanning the incidence of deep vein thrombosis was similar in the two groups. There was no increased incidence of excessive bleeding in patients on dextran though clinical impression suggested that some patients on dextran bled excessively. This trial showed that dextran 70 administered by intravenous drip during operation is effective in preventing pulmonary embolism and, in particular, reducing mortality from this cause. It seems to be as effective as subcutaneous heparin but is easier to administer and places less of a burden on nursing services.

Clinical Trials as Topic↗

Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability.

Polydisperse mixtures of dextran or Ficoll have been frequently used as molecular probes for studies of glomerular permselectivity because they are largely inert and not processed (reabsorbed) by the proximal tubules. However, dextrans are linear, flexible molecules, which apparently are hyperpermeable across the glomerular barrier. By contrast, the Ficoll molecule is almost spherical. Still, there is ample evidence that Ficoll fractional clearances (sieving coefficients) across the glomerular capillary wall (GCW) are markedly higher than those for neutral globular proteins of an equivalent in vitro Stokes-Einstein (SE) radius. Physical data, obtained by "crowding" experiments or measurements of intrinsic viscosity, suggest that the Ficoll molecule exhibits a rather open, deformable structure and thus deviates from an ideally hard sphere. This is also indicated from the relationship between (log) in vitro SE radius and (log) molecular weight (MW). Whereas globular proteins seem to behave in a way similar to hydrated hard spheres, polydisperse dextran and Ficoll exhibit in vitro SE radii that are much larger than those for compact spherical molecules of equivalent MW. For dextran, this can be partially explained by a high-molecular-size asymmetry. However, for Ficoll the explanation may be that the Ficoll molecule is more flexible (deformable) than are globular proteins. An increased compressibility of Ficoll and an increased deformability and size asymmetry for dextran may be the explanation for the fact that the permeability of the GCW is significantly higher when assessed using polysaccharides such as Ficoll or dextran compared with that obtained using globular proteins as molecular size probes. We suggest that molecular deformability, besides molecular size, shape, and charge, plays a crucial role in determining the glomerular permeability to molecules of different species.

Dextrans↗

Glomerular and postglomerular permselectivity to anionic dextrans in the dog.

Glomerular (G) and postglomerular (PG) capillary permselectivity to anionic dextran markers was investigated using the multiple-indicator-dilution (MID) technique in anesthetized mongrel dogs (n = 14). A bolus of solutes that included sulfated [3H]dextran (SO4d) homogeneous fractions 15.0-28.5 A Stokes-Einstein radius, 125I-albumin (plasma reference), [14C]inulin (G reference), and creatinine (interstitial reference) was injected into the left renal artery. Serial samples of left renal venous and urine outflows were rapidly collected. Sulfated [3H]dextran was 100% recovered, indicating no secretion or reabsorption. The urine recovery of the extracellular indicators was a measure of G extraction (EG). Mean EGSO4d/EGi (+/- SD) ranged from 0.82 +/- 0.03 to 0.48 +/- 0.02 for SO4d's 15.0-28.5 A and was invariant with renal plasma flow (F). These values were 30-50% less than the fractional EG for neutral [3H]dextrans. Postglomerular capillary extraction (EPG) was calculated from the renal vein outflow curve upslope ratios. EPGso4d/EPGcreat varied inversely with F, confirming PG diffusion limitation. Mean permeability-surface area (PS) product ratios PSSO4d/PSi (+/- SD) ranged from 0.98 +/- 0.01 to 0.55 +/- 0.04 for SO4d's 15.0-28.5 A and were consistently larger than values for neutral [3H]dextrans of the same molecular size. In contrast to G charge limitation to anionic solute flux, the PG capillaries demonstrate an increase in apparent permeability to anionic relative to neutral dextrans.

Albuminuria↗

Intravesical administration of EGF- dextran conjugates in patients with superficial bladder cancer.

OBJECTIVES: Overexpression of the epidermal growth factor receptor (EGFR) has been reported in bladder cancer and is a potential target for therapy with radionuclides. In this study, we investigated the binding of EGF-dextran-(99m)Tc to the EGFR. The aim of this study was to determine if intravesically administered EGF-dextran conjungate selectively accumulated in the tumor tissue and to correlate the uptake to tumor characteristics. METHODS: Eight patients received the conjugate intravesically for about 30 min followed by bladder irrigation and then transurethral resection. Radioactivity of the biopsy specimens from normal urothelium and tumor areas was measured in a gamma counter. RESULTS: Five patients received EGF-dextran-(99m)Tc, three received dextran-(99m)Tc and one received only (99m)Tc. The 5 patients who received the complete conjugate had a mean ratio of radioactivity between tumor and normal urothelium of 664:1 (range: 2.4-1,710). The dextran-(99m)Tc showed a slightly increased ratio and (99m)Tc did not bind at all. CONCLUSION: The results are encouraging and further studies are warranted to investigate if EGF-dextran could be effective as intravesical therapy, either conjugated with cystostatic drugs or labeled with suitable radionuclides.

Administration, Intravesical↗

Effect of dextran 40 on endothelial binding and vesicle loading of ferritin in rabbit aorta.

The effects of dextran 40 on endothelial binding and vesicle loading of cationized (CF, pl greater than 9.0) and anionic (AF, pl = 3.8 to 4.2) ferritins were investigated in the rabbit aorta. After two minutes of in situ perfusion, both ferritin species entered luminal vesicles and bound to the luminal endothelial membrane with a high surface density at vesicle necks. With CF, the presence of 5% dextran 40 did not change the fraction of vesicles loaded, the number of particles per vesicle, or the average density of particles bound to the luminal membrane, but did reduce the average density of particles adhering to vesicle necks. With AF, dextran 40 increased the percentage of vesicles filled, the average number of particles per loaded vesicle, the membrane particle density, the percentage of loaded vesicle necks, and the average density of particles adhering to vesicle necks. Application of gel chromatography and electrophoresis and determination of carbohydrates in the ferritin and dextran perfusates by the anthrone method after precipitation of the ferritin demonstrated that the dextran and ferritin did not conjugate. We hypothesize that the dextran binds to the endothelial membrane and increases its affinity to AF possibly by shielding negatively charged sites and that it binds in such a way as to offer little steric hindrance to AF particles entering vesicles.

Animals↗

PEGylated dextran as long-circulating pharmaceutical carrier.

Dextran-polyethylene glycol (PEG) conjugates were synthesized by activating dextran hydroxy groups with carbonyldiimidazole, introducing amino groups by attaching ethylenediamine, and reacting amino groups with a succinimidyl-activated derivative of PEG. Conjugates with an average of 12 and 21 PEG (5 kDa) residues per single dextran (73 kDa) molecule were prepared. These conjugates have circulation half-lives of 5.3 h and 7.0 h, respectively, compared to 4.0 h for non-PEGylated dextran. The modification of dextran with PEG inhibits the uptake of polymer by the major organ of the reticuloendothelial system, the liver. Dextran-PEG conjugates may represent a convenient platform for long-circulating pharmaceutical preparations.

Animals↗

Synthesis and characterization of pH-sensitive dextran hydrogels as a potential colon-specific drug delivery system.

pH-Sensitive dextran hydrogels were prepared by activation of dextran (T-70) with 4-nitrophenyl chloroformate, followed by conjugation of the activated dextran with 4-aminobutyric acid and cross-linking with 1,10-diaminodecane. The cross-linking efficiencies determined by mechanical measurements were in the range of 52-63%. Incorporation of carboxylpropyl groups in dextran hydrogels led to a higher equilibrium and faster swelling under high pH conditions. The swelling reversibility of hydrogels was also observed after repeated changes in buffers between pH 2.0 and 7.4. The slow rates of swelling and deswelling in response to changes in pH were attributed to the hydrophilic nature of dextran and formation of hydrogen bonds between the hydroxyl groups of dextran with water molecules. The pronounced effect of carboxylic acid content on degradation of hydrogels was observed after 4 h of incubation with dextranase and the influence significantly decreased after exposure to the enzyme for 8 h. The mechanism of bulk degradation of hydrogels under high swelling extent was substantiated using Coomassie blue protein assay. The release rate of bovine serum albumin from hydrogels was primarily determined by the swelling extent. The release rate was further enhanced by addition of dextranase in buffer solutions.

Colonic Diseases↗

Streptoccus mutans dextransucrase: purification, properties, and requirement for primer dextran.

We attempted to purify dextransucrase from S mutans strain 6715 to investigate its properties and determine if multiple species of the enzyme existed. It was concluded that the properties of this enzyme such as the pH (5.5), temperature (37 C) optimum, and Km for sucrose (3 mM) are very similar to those reported for S sanguis, S bovis, S mutans strain OMZ-176 isozymes, S mutans strain GS-5, and the single dextransucrase purified from S mutans strain HS-6. The IEF enzyme preparation consisted of two enzyme species, possibly differing in their ability to synthesize different dextran linkages. The minor enzyme activity demonstrated a strict primer dependency. Similarly, primer dependency has been reported for dextransucrases from S mutans, S sanguis, and L mesenteroides. S mutans strain 6715 dextransucrase also showed both the insertion and stepwise mechanisms for dextran synthesis. Sucrose was the sole glucose donor, whereas dextran was a specific, highly efficient glucose acceptor. The complex primer kinetics are not fully understood at this time and require further investigation. Without linkage analysis of the products of our enzymes, we can only postulate that each enzyme has a different function in the synthesis of interresidue and interchain alpha1-3 and alpha1-6 bonds. Insoluble dextran synthesis may involve a special enzyme mechanism characteristic of S mutans. This synthesis would require both enzymes, possibly in some aggregated form, with one enzyme synthesizing endogenous primer dextran. This endogeneous primer or some cell wall polysaccharide could stimulate both enzymes to rapidly synthesize heterogeneously linked insoluble dextran.

Chemical Phenomena↗

The effect of dextran on the pharmacokinetics of lignocaine during epidural anaesthesia.

The clinical significance of combining local anaesthetics with dextran is controversial. Although a number of investigators have found that dextran can prolong the action of local anaesthetics, others have not been able to demonstrate any significant change in the duration of anaesthesia. A study was carried out to investigate the effect of dextran on the pharmacokinetic behaviour of lignocaine during epidural anaesthesia in 20 adult male patients, who were randomly allocated to two treatment groups: group 1 (n = 10) was given lignocaine-dextran; group 2 (n = 10) was given lignocaine-saline. The results of the study demonstrated that the addition of dextran to epidural lignocaine significantly slowed systemic absorption of lignocaine as indicated by a smaller absorption rate constant, a reduced peak plasma concentration (Cmax), a delayed time to reach Cmax. and a smaller area under the concentration-time curve. The observed findings suggest that dextran reduces vascular uptake of lignocaine from epidural space and that it may prolong the duration of action. The significance of these findings on systemic toxicity, dosage and onset of action of lignocaine need to be investigated.

Adult↗

Efficacy of dextran solutions in vascular surgery.

The purpose of this paper is to discuss the role and efficacy of dextran in vascular procedures using evidence-based data from the review of surgical literature. A medline search using "dextran,'' "vascular surgery,'' and "antiplatelet therapy'' as keywords was performed for English-language articles. Further references were obtained through cross-referencing the bibliography cited in each work. Dextran is commonly used in carotid endarterectomy (CEA) patients where the embolic rate is reduced by 46%, resulting in fewer procedure-related strokes. As a prophylactic agent against thrombosis, multiple randomized studies have reported its benefit over other antithrombotic medications. Dextran is also particularly useful in "difficult'' infragenicular lower extremity bypasses where artificial grafts (such as polytetrafluoroethylene [PTFE] or umbilical vein) are used in the setting of poor outflow vessels, or those with composite grafts and small-caliber venous conduits. Distal bypasses with adjunctive procedures (eg, arteriovenous fistula or anastomotic cuffs) also have a better outcome with the addition of dextran. Dextran has numerous important implications in vascular surgery, in particular with CEA patients or "difficult'' infragenicular bypasses. Its effectiveness with endovascular stents remains unknown.

Acute Kidney Injury↗

Morphological alterations of exogenous surfactant inhibited by meconium can be prevented by dextran.

BACKGROUND: Surfactant dysfunction due to inhibition is involved in the pathophysiology of meconium aspiration syndrome. Dextran addition has been shown to reverse exogenous surfactant inactivation by meconium, but the precise mechanisms and the morphological correlate of this effect are yet unknown. Morphological surfactant analysis by transmission electron microscopy (TEM) and stereology allows the differentiation of active (large aggregates = LA) and inactive (small aggregates = SA) subtypes. METHODS: To determine the in vitro effects of meconium and dextran addition on the morphology of a modified porcine natural surfactant (Curosurf), Curosurf samples were either incubated alone or together with meconium or with meconium and dextran, fixed and processed for TEM. Volume fractions of surfactant subtypes [lamellar body-like forms (LBL), multilamellar vesicles (MV), unilamellar vesicles (UV)] were determined stereologically. RESULTS: All preparations contained LBL and MV (corresponding to LA) as well as UV (corresponding to SA). The volume fraction of UV increased with addition of meconium and decreased with further addition of dextran. Correspondingly, the UV/(LBL+MV) ratio (resembling the SA/LA ratio) increased when meconium was added and decreased when dextran was added to the surfactant-meconium mixture. CONCLUSION: Meconium causes alterations in the ultrastructural composition of Curosurf that can be visualized and analyzed by TEM and stereology. These alterations resemble an increase in the SA/LA ratio and are paralleled by an increase in minimum surface tension. Dextran prevents these effects and may therefore be a useful additive to exogenous surfactant preparations to preserve their structural and functional integrity, thereby improving their resistance to inactivation.

Biological Products↗

In vitro characteristics and in vivo plasma disposition of cisplatin conjugated with oxidized and dicarboxymethylated dextrans.

In vitro release behavior and cytotoxic activity, and in vivo plasma disposition of newly synthesized macromolecular derivatives of cisplatin (CDDP) were investigated and compared with CDDP. The derivatives included oxidized dextran conjugate of CDDP (OX-Dex/CDDP) and dicarboxymethylated dextran conjugate of CDDP (DCM-Dex/CDDP). In vitro release of platinum complex from dextran conjugated CDDP was determined by an equilibrium dialysis method. These dextran conjugates showed sustained release of the platinum complex. In vitro release half-life for DCM-Dex/CDDP was significantly longer (4.5 times) than that for OX-Dex/CDDP. In vitro cytotoxic activity of CDDP and dextran conjugated CDDP against colon 26, mouse colon cancer cell line, was measured using the MTT assay method. OX-Dex/CDDP showed a similar cytotoxic activity to CDDP. However, both cytotoxic activities were markedly decreased when preincubated with the medium containing serum. On the other hand, DCM-Dex/CDDP retained residual cytotoxic activity at a significantly higher level than OX-Dex/CDDP after preincubation with the medium containing serum, although it showed the lowest cytotoxic activity. This indicated longer maintenance of the in vitro antitumor activity of DCM-Dex/CDDP in serum compared with OX-Dex/CDDP. Plasma disposition of CDDP and dextran conjugated CDDP was determined by intravenous administration to rats. Although the total platinum plasma concentration-time profile for OX-Dex/CDDP was similar to that for CDDP, its markedly higher profile was achieved when DCM-Dex/CDDP was administered. The values of the total platinum AUC and MRT, where AUC is the area under the platinum concentration-time curve and MRT is the mean residence time, for DCM-Dex/CDDP were 11.2 times and 4.8 times significantly higher than with OX-Dex/CDDP in plasma, respectively. DCM-Dex/CDDP also showed a significantly lower total clearance compared with OX-Dex/CDDP. These results from the in vivo experiments revealed that retention of DCM-Dex/CDDP in blood circulation was much greater than that for OX-Dex/CDDP. DCM-Dex/CDDP thus has potential as a macromolecular derivative of CDDP for passive tumor targeting.

Animals↗

Characterization of dextran sulfate-induced guinea pig tracheal plasma extravasation.

We examined the effect of dextran sulfate on guinea pig tracheal vascular permeability. I.v. injection of dextran sulfate (10-100 mg/kg) with captopril (1 mg/kg) induced guinea pig tracheal plasma extravasation. The i.v. administration of bradykinin (0.8-8 micrograms/kg) with captopril (1 mg/kg) also induced plasma extravasation. Bradykinin B2 antagonists, D-Arg[Hyp3-Thi5-D-Tic7-Tic8]-bradykinin (NPC 16731) and D-Arg[Hyp3-Thi5-D-Tic7-Oic8]-bradykinin (Hoe 140), reduced both dextran sulfate (32 mg/kg)- and bradykinin (2.5 micrograms/kg)-induced tracheal plasma extravasation in a dose-dependent manner. However, a cyclooxygenase inhibitor, indomethacin (1 mg/kg), and a neurokinin antagonist, [N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl )- propionyl]-L-threonyl]tyrosyl-L-leucynyl]-D-phenylalanyl]-L-a llo-threonyl]-L-asparaginyl]-L-serine-D-lactone] (FK 224) (1 mg/kg), had no effect on tracheal plasma extravasation induced by dextran sulfate and bradykinin. Dextran sulfate (32 mg/kg) with captopril (1 mg/kg) greatly increased the bradykinin level in guinea pig plasma. This evidence suggests that dextran sulfate releases bradykinin in guinea pig plasma and causes guinea pig tracheal plasma extravasation via the activation of bradykinin B2-receptors.

Analysis of Variance↗

Molecular characteristics of bovine serum albumin-dextran conjugates.

Bovine serum albumin (BSA)-dextran conjugates were prepared by using the Maillard reaction; depending on the ratio of dextran to BSA used, about 0.5-1 mol of dextran could be bound to 1 mol of native BSA. SDS-PAGE patterns revealed that BSA and dextran had been covalently bonded. Structural analyses by fluorescence spectroscopy and circular dichroism indicated that the BSA surface in each conjugate was covered with dextran without any great disruption of the native conformation. The conjugates could be grouped into two fractions on the basis of the weight-average molecular mass measured: the main fraction at 1.95-2.35 x 10(5) g/mol and a less-abundant fraction with aggregates greater than 1.50 x 10(6) g/mol. High-performance size-exclusion chromatography in conjunction with multi-angle laser light scattering detection revealed that the BSA-dextran conjugates prepared by using the Maillard reaction had various molar masses and radii.

Chromatography, Gel↗

An ecto-ATPase activity present in Leishmania tropica stimulated by dextran sulfate.

In this study we report the effects of sulfated polysaccharides on the ecto-ATPase activity of intact cells of Leishmania tropica. Increasing concentrations of dextran sulfate stimulated progressively the ecto-ATPase activity, but did not modify other ecto-enzymes present on the surface of this parasite, such as 5'nucleotidase, 3'nucleotidase and a membrane-bound acid phosphatase activity. This stimulation was not observed when other sulfated polysaccharides such as chondroitin sulfates and heparin were tested. It depends on size and charge of the dextran sulfated molecule. When the cells were incubated in the presence of dextran sulfate Mr 8,000; 40,000 and 500,000 the stimulation of the ecto-ATPase activity was 11%; 23%; and 63%, respectively, and the stimulation was not observed when desulfated dextran (Mr 40,000) was used. The effects of dextran sulfate also depend on pH of the medium. At pH 7.5, the stimulation was over 60%, whereas at pH 8.5 only 25%. The effects of dextran sulfate 500,000 on the ecto-ATPase activity was totally abolished by spermidine and partially by putrescine, two polyamines synthesized and released by Leishmania.

4-Nitrophenylphosphatase↗

Preferential adsorption of cationic anti-DNA antibodies with immobilized polyanionic compounds, dextran sulfate.

It has been shown that cationic anti-DNA antibodies have nephritogenic potential in murine models of lupus nephritis. More recently, we have reported that there is a close relationship between the presence of circulating cationic anti-DNA antibodies and the development of lupus nephritis in humans, and that the cationic anti-DNA antibodies bind to heparan sulfate, a major glycosaminoglycan in glomerular basement membrane, much better than neutral anti-DNA antibodies. This suggests that cationic anti-DNA antibodies of the IgG class may be responsible for development of nephritis in vivo in patients with systemic lupus erythematosus. In this study, we first studied reactivity of anti-DNA antibodies with a panel of glycosaminoglycans in vitro using ELISA methods, and found that anti-DNA antibodies cross-react with dextran sulfate, hyaluronic acid and chrondroitin sulfate. The reactivity and selectivity of dextran sulfate with anti-DNA antibodies was confirmed by in vitro immunoadsorption of the patient's sera with dextran sulfate-fixed column; incubation of auto-antibody-positive sera with dextran sulfate cellulose column removed anti-DNA, but not anti-RNP, anti-Sm, anti-SSA and anti-SSB antibodies from the sera in vitro. Of note is that dextran sulfate cellulose column absorbed exclusively, if not all, cationic anti-DNA antibodies in their sera. Nonspecific binding of total immunoglobulins as well as total proteins to the column was marginal. It has been suggested that cationic anti-DNA antibodies in sera of patients with refractory lupus nephritis could be efficiently removed by apheresis using dextran sulfate column.

Adolescent↗

Mechanism of dextran transport across rabbit intestinal tissue and a human colon cell-line (CACO-2).

The in vitro permeabilities of 14C labeled dextrans (10, 40, and 70 kD) were calculated from mass transport across Peyer's patches and non-patch tissues derived from rabbit jejunum, and a human colon cell line (Caco-2) grown as a monolayer on polycarbonate filters. Size distribution of dextrans did not change upon transport as judged from size exclusion chromatography. Permeabilities decreased in a size-dependent manner. Ranking of permeabilities for dextran 10 and 40 kD were: Caco-2 > non-patch tissue > Peyer's patches; while dextran 70 kD demonstrated no difference among the barriers. Tissue resistance, expressed as 1/(permeability.tissue thickness) was virtually the same in Peyer's patches and non-patch tissue, suggesting that tissue thickness and not interaction determines the difference in permeability. ATP depletion with ouabain, Na(+)-azide and 2-deoxy-D-glucose, and low temperature (4 degrees C) did not result in reduced permeabilities suggesting passive transport. The results suggest that the investigated intestinal barriers transport dextrans in a similar fashion independent of their source. However, comparison of the ratios dextran 10 kD/mannitol and PEG 900/mannitol between rabbit tissue and Caco-2 monolayers suggests Caco-2 monolayers may serve as a model to study absorption potential of potentially harmful compounds in coeliac disease, gastroenteritis, and colon carcinoma.

Adenocarcinoma↗