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PubMed2002

Water sorption and glass transition behaviors of freeze-dried sucrose-dextran mixtures.

The water sorption and glass transition behaviors of freeze-dried disaccharide-polysaccharide mixtures at various contents were investigated at relative humidities (RHs) of 0, 11, 23, and 33%. Sucrose and three types of dextrans, which differ in molecular weight, were used as model di- and polysaccharides, respectively. The relationship between the dextran and water contents of the sucrose-dextran mixture at different constant RHs indicated that a mixture of sucrose and dextran was lower than that calculated by the Lang and Steinberg mass balance equation. In the RH range of 0-23%, the glass transition temperature, T(g), increased to a considerable extent when the dextran content was equal to or higher than 50%, while the increase in T(g) at dextran contents lower than 50% was small. A marked increase in T(g) was observed at RH 33% for dextran contents of 0-25% as well as in the range above 50%. This suggests that the physical stability of the highly hydrated amorphous disaccharide is effectively strengthened by the addition of a small amount of polysaccharide. These tendencies were similar for the three dextrans of different molecular weights. Furthermore, it was demonstrated that the addition of a small amount of dextran is quite effective in preventing the collapse of amorphous sugar during freeze drying.

Adsorption↗

PubMed1992

Molecular-weight-dependent pharmacokinetics of fluorescein-labeled dextrans in rats.

The dependency of the pharmacokinetics of fluorescein-labeled dextrans on M(r) was studied in adult Sprague-Dawley rats. Single intravenous doses (5 mg/kg) of the dextrans with M(r) of 4000, 20,000, 40,000, 70,000, or 150,000 and single oral doses (50 mg/kg) of the dextrans with M(r) of 4000, 20,000, or 40,000 were administered to different groups of rats. A specific and sensitive high-performance, size-exclusion chromatographic method was used to measure the concentrations of the dextrans in serial serum and urine samples, and the relevant kinetic parameters were calculated. After intravenous administration, the profiles of the concentration of dextran in serum versus time for all the studied dextrans exhibited an apparent biexponential decline, with all the calculated kinetic parameters being dependent on M(r). However, the degree of dependency varied for different parameters. Among the calculated kinetic parameters, renal clearance and volume of distribution values were affected the most and least, respectively, by the differences in M(r). Furthermore, we observed a clear separation between the labeled dextrans with M(r) less than or equal to 20,000 and those with M(r) greater than or equal to 40,000 with respect to their concentrations in serum and kinetic parameters. After oral administration, the dextrans could not be detected in serum, and on the basis of urine data, only negligible amounts of the macromolecules were absorbed into the systemic circulation (less than 0.4% of the dose). The data presented here may be used in the future design of microvascular and drug delivery studies with dextrans.

Animals↗

PubMed1993

Dextran's antithrombotic properties in small arteries are not altered by low-molecular-weight heparin or the fibrinolytic inhibitor tranexamic acid: an experimental study.

In two separate blind, randomized studies, 48 rabbits were divided into five groups. Three treated groups received dextran 70 (0.51 g/kg) as a single injection, dextran 70 combined with low molecular-weight heparin (LMWH) (560 IU/kg as anti-FXa and 140 IU/kg as APTT in 3 hr), and dextran 70 plus tranexamic acid (14 mg/kg) following severe arterial trauma (arteriotomy/intimectomy). Two control groups received the same amount of saline. The bleeding times from the arteriotomy were recorded, and patency rates and the weight of thrombotic materials were registered 2 hr after reperfusion of the trauma region. The bleeding times in three treated groups, all including dextran, were significantly prolonged compared to the control groups (P < 0.05 or 0.01). The patency rates of treated groups, which were 100% (18/18 vessels patent) in the dextran-treated group, 90% (18/20 vessels patent) in the dextran+LMWH group and 95% 19/20 vessels patent) in dextran+tranexamic acid group, were significantly higher than those of their control groups (55-67% patent vessels) (p < 0.05 or 0.01). The mean weights of thrombotic materials were significantly reduced in the treated groups compared to the corresponding control groups (p < 0.01). In conclusion, dextran 70 in an ordinary dose exerted such a profound antithrombotic effect (100% patency) in small traumatized arteries that the addition of a high dose of LMWH could not further improve patency rates or decrease thrombotic materials but did not prolong vessel bleeding times compared to the single dextran treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Dextran magnetite as a liver contrast agent.

The superparamagnetic particle dextran magnetite was studied as a liver tumor contrast agent for magnetic resonance imaging (MRI). The effects of dextran magnetite on the longitudinal (T1) and transverse (T2) relaxation times in liver, spleen, and an implanted rat liver tumor were measured at 0.47 T (IBM/Bruker PC-20 relaxometer) over the dose range of 23 to 69 mumol Fe/kg. Dextran magnetite substantially reduced the T2 of the liver and spleen, but not of the tumor, thereby providing a basis for improved tumor imaging. The T1 of the tumor was not affected following injection of dextran magnetite in the dose range studied, while the spleen T1 was reduced substantially more than the T1 of the liver. Histological studies using the iron reaction for Prussian blue clearly showed dextran magnetite in the liver and spleen, but not in the tumor. While dextran magnetite was sequestered in macrophages in both liver and spleen, the distribution in the liver was more diffuse (70 microns average particle separation) than that in the spleen (25 microns separation). The lack of a T1 effect in the liver is consistent with the fact that a majority of the water in the tissue cannot diffuse to the relaxational centers on the time scale of the liver's intrinsic T1 (280 ms). In the spleen, however, the dextran magnetite is more densely packed in the red pulp allowing a significant fraction of the water to be relaxed by a T1 mechanism. Spin-echo images of the implanted tumor (mammary adenocarcinoma. R3230AC) in the livers of Fischer 344 rats were obtained at 0.50 T (Siemens Magnetom). The tumor-to-liver contrast was improved for both T1 and T2-weighted spin-echo images after intravenous injection of the dextran magnetite contrast agent. The contrast determined from these images agreed with that predicted by the measured T1 and the T2 (Hahn spin-echo) values. In addition, gradient-echo T2-weighted images with good contrast were obtained in a much shorter imaging time than was needed for T2-weighted spin-echo images. These results demonstrate that the MRI contrast enhancement observed with dextran magnetite is based on its selective uptake and distribution in the macrophages in the liver and spleen and that this agent has substantial potential as a superparamagnetic MR contrast agent.

Adenocarcinoma↗

PubMed1994

Determination of the number of sucrose and acceptor binding sites for Leuconostoc mesenteroides B-512FM dextransucrase, and the confirmation of the two-site mechanism for dextran synthesis.

In previous studies on dextransucrase using pulse and chase experiments with [14C]sucrose, Robyt et al. [Arch. Biochem. Biophys. 165 (1974) 634-640] proposed a two-site insertion mechanism to explain the data for the synthesis of dextran. To further establish the validity of the two-site mechanism, the number of sucrose binding sites at the active site have been determined by using equilibrium dialysis with 6-deoxysucrose, a strong competitive inhibitor for dextransucrase. A ligand binding plot gave a straight line that indicated there were two sucrose binding sites at the active site. A similar experiment was performed using the acceptor, maltose. The ligand binding plot for maltose also gave a straight line and indicated that there was one acceptor binding site at the active site. These results corroborate the proposed two-site mechanism for dextran synthesis. To further test the two-site mechanism, dextransucrase was partially inactivated to varying extents by reaction with diethylpyrocarbonate, which chemically modifies essential active-site histidines. The various partially inactivated enzymes were assayed for dextran synthesis and for the synthesis of maltose acceptor products. A plot of the log of the relative percentage of dextran synthesized and acceptor products synthesized against varying degrees of enzyme inactivation showed that the synthesis of dextran decreased to a greater extent than did the decrease of the synthesis of acceptor product. The proposed mechanism requires two sucrose sites for the synthesis of dextran and only one sucrose site for the synthesis of acceptor product. When one site is modified, the synthesis of dextran stops, but the synthesis of acceptor products can continue at the other site. Thus, the greater loss of dextran synthesis in comparison with the lesser loss of acceptor product synthesis by enzymes modified to varying degrees, gives further evidence for the two-site mechanism for dextran synthesis.

Binding Sites↗

PubMed1999

Effects of dextran on tracheal mucociliary velocity in dogs in vivo.

We have previously shown that dextran (molecular weight 4kDa) is a potential mucolytic agent, reducing the viscoelasticity and spinnability of cystic fibrosis (CF) sputum and improving its mucociliary clearability during in vitro testing. We wished to see whether low molecular weight (LMW) dextran had similar effects on mucus rheology when administered by aerosol to living dogs, and whether the administration of dextran increased the rate of mucociliary clearance. Healthy mongrel dogs were anesthetized with pentobarbital and intubated. After a 30-min Ringer aerosol delivery during spontaneous breathing, tracheal mucociliary velocity (TMV by charcoal marker particle transport) was measured under bronchoscopic control, and mucus for viscoelasticity analysis (magnetic rheometer) was collected by the endotracheal tube method. Then LMW dextran in Ringer vehicle was delivered by aerosol via the endotracheal tube, followed by the same procedures. We performed eight experiments in eight dogs, involving 30 min administrations of dextran aerosol; all dogs received inhalations of 20 mg/ml, 65 mg/ml, and 200 mg/ml dextran. Compared with Ringer control, TMV increased to 145% of control (P=0.0417) at 65 mg/ml dextran. Mucus viscoelasticity (G*) significantly decreased to 19% of control (P=0.0426) at 65 mg/ml. This in vivo study supports our previous in vitro testing, that LMW dextran decreases the mucus viscoelasticity and increases the rate of mucociliary clearance. We estimate the dosage received by aerosol at 65 mg/ml to be within the effective concentration range studied in vitro, i.e. 10-15 mg/ml final concentration. The results are consistent with the proposed mechanism that the saccharide moieties in LMW dextran compete for hydrogen bonding sites with other mucous glycoproteins. These new hydrogen bonds are structurally and rheologically ineffective, thus reducing the overall cross-link density, and making the mucus more easily cleared by ciliary and cough mechanisms.

Administration, Inhalation↗

PubMed2006

Beta-relaxation of insulin molecule in lyophilized formulations containing trehalose or dextran as a determinant of chemical reactivity.

PURPOSE: The purpose of this study was to elucidate whether the degradation rate of insulin in lyophilized formulations is determined by matrix mobility, as reflected in glass transition temperature (Tg), or by beta-relaxation, as reflected in rotating-frame spin-lattice relaxation time (T1rho). METHODS: The storage stability of insulin lyophilized with dextran was investigated at various relative humidities (RH; 12-60%) and temperatures (40-90 degrees C) and was compared with previously reported data for insulin lyophilized with trehalose. Insulin degradation was monitored by reverse-phase high-performance liquid chromatography. Furthermore, the T1rho of the insulin carbonyl carbon in the lyophilized insulin-dextran and insulin-trehalose systems was measured at 25 degrees C by 13C solid-state NMR, and the effect of trehalose and dextran on T1rho was compared at various humidities. RESULTS: The degradation rate of insulin lyophilized with dextran was not significantly affected by the Tg of the matrix, even at low humidity (12% RH), in contrast to that of insulin lyophilized with trehalose. The insulin-dextran system exhibited a substantially greater degradation rate than the insulin-trehalose system at a given temperature below the Tg. The difference in degradation rate between the insulin-dextran and insulin-trehalose systems observed at 12% RH was eliminated at 43% RH. In addition, the T1rho of the insulin carbonyl carbon at low humidity (12% RH) was prolonged by the addition of trehalose, but not by the addition of dextran. This difference was eliminated at 23% RH, at which point the solid remained in the glassy state. These findings suggest that the beta-relaxation of insulin is inhibited by trehalose at low humidity, presumably as a result of insulin-trehalose interaction, and thus becomes a rate determinant. In contrast, dextran, whose ability to interact with insulin is thought to be less than that of trehalose, did not inhibit the beta-relaxation of insulin, and thus, the chemical activational barrier (activation energy) rather than beta-relaxation becomes the major rate determinant. CONCLUSIONS: Beta-relaxation rather than matrix mobility seems to be more important in determining the stability of insulin in the glassy state in lyophilized formulations containing trehalose and dextran.

Chemistry, Pharmaceutical↗

PubMed1994

Dextran sulfate binding to isolated rat glomeruli and glomerular basement membrane.

The binding of dextran sulfate to isolated glomeruli and glomerular basement membrane has been studied and compared to the glomerular uptake of dextran sulfate during isolated kidney perfusion. Two binding sites for [3H]dextran sulfate to isolated glomeruli could be identified at 37 degrees C; an high affinity site (KA = 4.76 x 10(6) M-1) (4.4 x 10(10) molecules/glomerulus) and a low affinity site (KA = 5.8 x 10(4) M-1) (2.0 x 10(11) molecules/glomerulus) whereas at 4 degrees C there was only an high affinity binding site (KA = 1.43 x 10(6) M-1) (7 x 10(10) molecules/glomerulus). The glomerular binding of dextran sulfate appears to be to cellular elements as the binding sites were not present in purified glomerular basement membrane which effectively did not bind dextran sulfate. The binding of dextran sulfate to isolated glomeruli was far in excess of that found associated with glomerular uptake during isolated kidney perfusion. The difference has been discussed in terms of the different capillary wall surfaces exposed to the dextran sulfate and the concentration gradients that may exist in the two types of experiments. The structural integrity of the glomerulus is also important in governing the amount of binding as structural disintegration through freeze-thawing and sonication revealed more binding sites. These data may suggest a specific distribution of binding sites and specific transglomerular transport pathways where many of these sites are not exposed. The nature of binding [3H]dextran sulfate to isolated glomeruli was different to isolated perfused kidney glomerular uptake when studied in terms of the kinetics of exchange with unlabelled dextran sulfate. This exchange data suggests a passive binding mechanism in isolated glomeruli whereas in isolated kidney perfusion the nature of the exchange would suggest a glomerular intracellular uptake (Tay, M., et al. (1991) Am. J. Physiol. 260, F549-F554).

Animals↗

PubMed2004

Gadolinium-DTPA-dextran: a macromolecular MR blood pool contrast agent.

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging blood pool agents offer numerous advantages for vascular and tumor imaging. The purpose of this study was to test gadolinium-diethylenetriaminepentaacetate-dextran ([Gd]DTPA-dextran) as a new water soluble macromolecular blood pool agent for MR imaging. MATERIALS AND METHODS: [Gd]DTPA-dextran (187 gadolinium atoms per dextran, molecular weight 165 kD, diameter 17.6 nm) was synthesized. Fifteen anesthetized New Zealand White rabbits with thigh VX2 tumors were scanned in a knee coil at 1.5T. Coronal 3D MR angiographic sequences were obtained before and at several time points up to 72 hours after the intravenous bolus injection of [Gd]DTPA-dextran providing gadolinium at either 0.05 (n = 4) or 0.1 mmol/kg (n = 8) or [Gd]DTPA-bismethylamide (BMA) providing gadolinium at 0.1 mmol/kg (n = 3). Time enhancement curves for aorta, cava, and tumor rim were compared by univariate General Linear Model. RESULTS: Contrast enhancement of cava and aorta relative to a water phantom were significantly greater at all time points after either dose of [Gd]DTPA-dextran than after [Gd]DTPA-BMA (P < 0.01). Tumor rim enhancement was less intense for either dose of [Gd]DTPA-dextran at peak than for [Gd]DTPA-BMA (P < 0.05). Tumor rim enhancement with both doses of [Gd]DTPA-dextran became equivalent to that of [Gd]DTPA-BMA at one hour and was greater at 24 hours (P < 0.05). CONCLUSION: [Gd]DTPA-dextran is a new macromolecular MR contrast agent that can be synthesized to carry a high density of gadolinium atoms without intra-molecular cross-linking. It provides significantly greater vascular residence time than a conventional gadolinium chelate and shows promise for MR blood pool imaging.

Animals↗

PubMed2006

How does dextran sulfate prevent heat induced aggregation of protein? The mechanism and its limitation as aggregation inhibitor.

The effect of dextran sulfate on protein aggregation was investigated to provide the clues of its biochemical mechanism. The interaction between dextran sulfate and BSA varied with the pH values of the solution, which led to the different extent of aggregation prevention by dextran sulfate. Light scattering data with thermal scan showed that dextran sulfate suppressed BSA aggregation at pH 5.1 and pH 6.2, while it had no effect at pH 7.5. Isothermal titration calorimetric analysis suggested that the pH dependency of the role of dextran sulfate on BSA aggregation would be related to the difference in the mode of BSA-dextran sulfate complex formation. Isothermal titration calorimetric analysis at pH 6.2 indicated that dextran sulfate did not bind to native BSA at this pH, but interacted with partially unfolded BSA. While stabilizing native form of protein by the complex formation has been suggested as the suitable mechanism of preventing aggregation, our observation of conformational changes by circular dichroism spectroscopy showed that strong electrostatic interaction between dextran sulfate and BSA rather facilitated the denaturation of BSA. Combining the data from isothermal titration calorimetry, circular dichroism, and dynamic light scattering, we found that the complex formation of the intermediate state of denatured BSA with dextran sulfate is a prerequisite to suppress the aggregation by preventing further oligomerization/aggregation process of denatured protein.

Calorimetry↗

PubMed2005

Macroporous interconnected dextran scaffolds of controlled porosity for tissue-engineering applications.

Dextran hydrogels have been studied as drug delivery vehicles but not as scaffolds for tissue-engineering likely because previously synthesized dextran hydrogels had pores too small for cell penetration. Our goal was to create macroporous, interconnected dextran scaffolds. To this end, we took advantage of the liquid-liquid immiscibility of poly(ethylene glycol) and methacrylated dextran during radical crosslinking of the methacrylated moieties. By controlling the degree of methacrylate substitution on dextran, dextran molar mass and PEG concentration, macroporous hydrogels were created. The presence of PEG in solution had a significant effect on the final morphology of the dextran hydrogel leading to the formation of different types of structures, from microporous gel to macroporous gel-wall to a macroporous interconnected-beaded structure. A series of formulation diagrams were prepared which allowed us to determine which conditions led to the formation of macroporous interconnected-beaded scaffolds. Dextran macroporous interconnected-beaded gels had a high water content, between 89% and 94%, a homogeneous morphology, determined by scanning electron microscopy, with interconnected macroporous pores, as determined by protein diffusivity where the effective diffusion coefficients of BSA were calculated to be 3.1 x 10(-7)cm2/s for Dex-MA 40 kDa DS 5 and 1 x 10(-7)cm2/s for Dex-MA 6 kDa DS10, which are similar to that of BSA in water, 5.9 x 10(-7)cm2/s. Mercury intrusion porosimetry showed that the macroporous interconnected-beaded scaffolds had a bimodal distribution of macropores, with a median diameter of 41 microm, interconnected by throats, which had a median diameter of 11 microm. Together, these data suggest that the dextran scaffolds will be advantageous in applications that require an interconnected macroporous geometry, such as those of tissue engineering where cell penetration and nutrient diffusion are necessary for tissue regeneration.

Acrylates↗

PubMed2006

Beta-lactoglobulin-dextran Maillard conjugates: their effect on interfacial thickness and emulsion stability.

The influence of dextran molecular weight on the steric layer thickness and oil-in-water (O/W) emulsion flocculation stability of beta-lactoglobulin-dextran Maillard conjugates was investigated. Maillard conjugates were formed by reacting beta-lactoglobulin with various molecular weight dextrans (Mw = 18.5-440 kDa) under mild conditions (60 degrees C, 76% RH). Purified Maillard conjugates or beta-lactoglobulin were adsorbed onto latex spheres and the thickness of the adsorbed layer measured using photon correlation spectroscopy. The adsorbed layer thickness was 3 nm for beta-lactoglobulin alone. Attachment of dextran increased adsorbed layer thickness to 5 nm for the conjugate with low molecular weight dextran (Mw = 18.5 kDa) and 20 nm for that with high molecular weight dextran (Mw = 440 kDa). Enzymatic digestion of the adsorbed layers with dextranase reduced the layer to a thickness corresponding to that of beta-lactoglobulin alone. This suggests that the protein segment of the Maillard conjugate anchors the emulsifier to the interface. Attachment of dextran, irrespective of its molecular weight (18.5-440 kDa), increased the stability of emulsions against calcium induced flocculation, demonstrating that a low molecular weight dextran is sufficient for imparting high steric stability. The observation that the steric layer size was controlled by the dextran molecular weight, suggests that the results of layer thickness and emulsion stability should be universal across all globular proteins.

Dextrans↗

PubMed2000

Surface-immobilized dextran limits cell adhesion and spreading.

Dextran has recently been investigated as an alternative to polyethylene glycol (PEG) for low protein-binding, cell-resistant coatings on biomaterial surfaces. Although anti-fouling properties of surface-grafted dextran and PEG are quite similar, the multivalent properties of dextran are advantageous when high-density surface immobilization of biologically active molecules to low protein-binding surface coatings is desired. The preferred methods of dextran immobilization for biomaterial applications should be simple with minimal toxicity. In this report, a method is described for covalent immobilization of dextran to material surfaces which involves low residual toxicity reagents in mild aqueous reaction conditions. 70 kDa MW dextran was immobilized on glass and polyethylene terephthalate (PET) surfaces. 3T3 fibroblast cell adhesion was compared on untreated, aminated, and dextran-coated materials. Dextran coatings effectively limited cell adhesion and spreading on glass and PET surfaces in the presence of serum-borne cell adhesion proteins. With dextran-based surface coatings, it will be possible to develop well-defined surface modifications that promote specific cell interactions and perhaps better performance in long-term biomaterial implants.

3T3 Cells↗

PubMed1996

Pharmacokinetics of Dextran-70 in patients with cirrhosis and ascites undergoing therapeutic paracentesis.

BACKGROUND/AIM: Dextran-70 is frequently used as a plasma expander in patients with cirrhosis treated with large-volume paracentesis to prevent post-paracentesis hypovolemia, which is thought to develop after 24 h following the procedure. However, there are no studies on Dextran-70 pharmacokinetics in cirrhosis. METHODS: Nine patients with alcoholic cirrhosis and tense ascites treated with a 5-1 paracentesis were given 500 ml of Dextran-70. Blood samples to measure the plasma concentration of dextran were obtained 15 and 30 min, 1, 2, 3, 6, 12 and 24 h and 2 and 6 days after the end of the infusion. Nine healthy volunteers were studied in identical fashion after infusion of 100 ml of Dextran-70. The plasma concentration of dextran was determined by the anthrone method. A bicompartmental model was used to analyze the pharmacokinetic parameters. RESULTS: There were no significant differences between patients with cirrhosis and controls in the volume of distribution (7.7 +/- 0.6 vs. 7.3 +/- 1.21), half-life of the first and second component of plasma disappearance (2.96 +/- 0.69 and 80.3 5.9 h in patients with cirrhosis vs 2.82 +/- 0.69 and 67.1 +/- 10.7 h in controls). CONCLUSIONS: The pharmacokinetics of Dextran-70 in patients with cirrhosis and ascites after large-volume paracentesis is similar to that in controls. This may explain why Dextran-70 is less effective than albumin in preventing paracentesis-induced hypovolemia, which starts after most Dextran fraction has disappeared from plasma.

Ascites↗

PubMed1990

[Pharmacokinetics and changes in the physical properties of blood and urine after administration of dextran 60000].

A study was carried out to assess the changes induced by an infusion of dextran, molecular weight 60,000 daltons, in blood and urine. Plasma and urine dextran and serum protein concentrations, haematocrit, blood and urine viscosities, and blood oncotic pressure were measured in 10 consecutive male patients. Fifteen min after administration of 20 ml dextran 1000 (Promit), they were each given 500 ml (30 g) dextran 60 (Hemodex) over 30 min for plasma volume expansion. The measurements were carried out at the end of the infusion, and then at regular intervals over a 48 h period. The highest dextran blood concentrations were found at the end of the infusion, decreasing thereafter with a distribution half-life of 1.83 +/- 0.64 h, and an elimination half-life of 25.5 +/- 7.6 h. Haematocrit values decreased by 12%, and serum protein concentrations by 9.5%, after the end of the infusion. These changes remained significant for 9 h; they were probably due to the dilution effect of 500 ml of dextran. Colloid osmotic pressure was not significantly altered (20.7 +/- 4.7 mmHg vs. 23.1 +/- 5.1 mmHg 48 h after the end of the infusion). The colloid osmotic pressure due to dextran 60 compensated for the fall in protein concentration. A decrease in blood viscosity was found at different shear rates, despite dextran 60 being highly viscous. This could also be explained by a dilution effect. The highest degree of urinary excretion occurred 30 min after the end of the infusion, and lasted for 3 h. Forty-five percent of the total dextran dose had been excreted by the 48th hour.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Dextran modification of a Fab'--beta-lactamase conjugate modulated by variable pretreatment of Fab' with amine-blocking reagents.

The physical and pharmacological properties of proteins can be altered by chemical modification with polymers. Preliminary studies showed that attachment of oxidized dextran to the bacterial protein, beta-lactamase (beta L) effectively reduced in vivo immunogenicity in mice with no loss of enzymatic activity. This report describes a general method for differentially dextran modifying the Fab' component of a Fab'--beta-lactamase conjugate by the use of amine-blocking reagents. Methyl acetimidate (MeAcm) and the N-succinimidyl derivative of (methylsulfonyl)ethyl carbonate (NHS-Msc), reagents which can reversibly block primary amines, were used in model studies to modulate the level of available reactive amines on the F(ab')2 fragments of both the anti-carcinoembryonic antigen antibody, ZCE025, and the antitumor-associated glycoprotein-72 antibody, CC49. MeAcm had little or no effect on immunoreactivity and was maximally effective in modulating dextran attachment, while NHS-Msc was much less effective. A comparison of NHS-Msc and MeAcm is described. Treatment of F(ab')2 with 5-300 mM MeAcm prior to dextran treatment showed a proportional decline in the level of dextran attachment as well as intramolecular cross-linking of the protein by the dextran polymers (6 kDa or 33-mer). A conjugate of beta L coupled to MeAcm-treated ZCE025 Fab' [reduced F(ab')2] was constructed under standard conditions using sulfosuccinimidyl N-[(4-carboxycyclohexyl)methyl]maleimide. After dextran modification, this conjugate maintained good immunoreactivity and enzymatic activity. Biodistribution studies in tumor-bearing nude mice of dextranated and nondextranated conjugate showed comparable overall distribution profiles except that the clearance of the dextranated conjugate from both blood and tumor was delayed about 48-72 h.

Animals↗

PubMed1999

A study of dextran production from maltodextrin by cell suspensions of Gluconobacter oxydans NCIB 4943.

This study investigated dextran synthesis from a commercial maltodextrin substrate using cell suspensions of G. oxydans NCIB 4943 as catalysts. Experiments were arranged according to a central composite statistical design. The effects of substrate concentration (10-100 g l-1), cell concentration (0.32-32.0 g wet weight l-1), time of reaction (8-48 h) and pH (3.5-5.5), each at three levels, on dextran yield and dextran molecular weight (MW), were investigated. Response surface methodology was used to assess factor interactions, and empirical models describing the two responses were fitted. Most of the variance in dextran yield could be explained by the fitted model (R2 = 0.96). Dextran yield ranged from 1.21 to 41.69%. The presence of significant negative quadratic effects of cell concentration and time indicated that dextran yield reached a plateau and thus, optimum levels of cell concentration and time could be identified to maximize dextran yield. Dextran MW ranged from 6.6 to 38 kDa and was characterized by the significant interactions of reaction time with substrate concentration and cell concentration. The model, however, could account for only 60% of the variance in dextran MW. Possible reasons for this are discussed.

Culture Media↗

PubMed2003

Effects of oxypolygelatin and dextran 70 on hemostatic variables in dogs.

OBJECTIVE: To evaluate and compare coagulation variables following the administration of oxypolygelatin and dextran 70 to clinically healthy dogs. STUDY DESIGN: Randomized cross-over experimental study. ANIMALS: A total of eight healthy adult female Beagles aged 2-4 years old and weighing 11.8 +/- 2.7 kg. METHODS: The dogs received a 15-minute intravenous (IV) infusion of 5 mL kg-1 oxypolygelatin or 10 mL kg-1 6% dextran 70. Before (PRE) and at 2, 5, and 24 hours after administration, packed cell volume (PCV), total solids concentration (TS), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen concentration (FIB), platelet numbers (Plat), factor VIII coagulant activity (VIII:C), von Willebrand factor antigen concentration (vWf:Ag) and platelet function and buccal mucosal bleeding time (BMBT) were measured. Platelet function was assessed using aggregation and by measuring ATP release from aggregating platelets over 6 minutes, with 20, 10, and 5 micro m ADP and 5 and 10 micro g of collagen mL-1 as platelet activation agonists. RESULTS: All baseline values were within our normal ranges, except for one dog that had low vWf:Ag PRE values prior to both dextran and oxypolygelatin administration. Following dextran and oxypolygelatin administration, the PCV and TP were significantly (p < 0.05) decreased. Plat, FIB, and vWf:Ag decreased, while BMBT and VIII:C increased following dextran administration. Dextran also caused a significant decrease in platelet aggregation in response to ADP. Oxypolygelatin caused a significant decrease in vWf:Ag, Plat, and FIB compared to PRE values. The total amount of ATP released, standardized to platelet number, did not vary significantly for either group at any sampling time from PRE values. No significant changes from PRE values were noted at any time in either group for PT or APTT. CONCLUSION: At the doses administered, both dextran and oxypolygelatin can interfere with hemostatic variables in healthy dogs, but dextran's effect is more profound and prolonged when compared to oxypolygelatin. CLINICAL RELEVANCE: Oxypolygelatin causes fewer hemostatic abnormalities when compared to dextran, making it a superior colloid for administration at the doses tested.

Animals↗