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Biomedical subjects

R Langer

Publications and source records attributed to R Langer.

At least 505 records · Page 28Linked to original sources
PubMed1986

Oral heparin results in the appearance of heparin fragments in the plasma of rats.

We have previously shown that angiogenesis inhibition and tumor regression can be accomplished by combinations of heparin or heparin fragments with cortisone [Folkman, J., Langer, R., Linhardt, R. J., Haudenschild, C. & Taylor, S. (1983) Science 221, 719-725]. Oral heparin was also effective in combination with cortisone. We now show that a single oral dose of [35S]heparin or [3H]heparin (15,000 units/kg) results in continuous release of radioactive material into the bloodstream for at least 12 hr. This is associated with the presence of anti-factor Xa activity at a level of approximately equal to 0.1 unit/ml. The radioactive material is identified as oligo-, di-, and monosaccharides by its behavior in chromatographic systems, its possession of anti-factor Xa activity, and the effect of treatment with bacterial heparinase. The heparin fragments are extensively metabolized to fragments without anti-factor Xa activity that are readily subject to urinary excretion.

Administration, Oral↗
PubMed1986

Controlled release of insulin from polymer matrices. In vitro kinetics.

A biocompatible system was developed that permits continuous release of biologically active insulin from small polymer matrices. Powdered insulin particles were incorporated into an ethylene-vinyl acetate copolymer matrix. The presence of particulate insulin resulted in a matrix composed of tortuous channels and constricted pores through which release occurred. When aqueous release media permeated the matrix, the insulin dissolved and diffused slowly through this tortuous network. The large concentration of insulin within the matrix provided the driving force for release. Release kinetics from these insulin polymer matrices were enhanced by increasing the insulin solubility, the insulin powder particle size, the loading of insulin within the matrix, and the porosity of the matrix. Appropriate geometric design of the polymer matrix resulted in near-constant insulin release rates.

Delayed-Action Preparations↗
PubMed1986

Controlled release of insulin from polymer matrices. Control of diabetes in rats.

The controlled release of insulin from ethylene-vinyl acetate copolymer matrices was demonstrated for over 100 days in vivo. The matrices were designed to release sodium insulin at near-constant rates. These 0.06-cm3 implants were coated completely with an impermeable layer of polymer. An aperture was drilled in the center of one face of the matrix, restricting release through this opening. These devices were implanted into 13 streptozocin-induced diabetic rats. Plasma glucose concentrations fell from 386 +/- 18 to 119 +/- 35 mg/dl (mean +/- SEM), and urinary glucose was eliminated. Thee parameters were controlled for up to 105 days by a single implant. Glycosylated hemoglobin concentrations measured 90 days after implantation were 3.86 +/- 0.11% for the polymer-treated rats, 3.10 +/- 0.18% for the normal controls, and 5.42 +/- 0.33% for the diabetic controls. The average weight gain of the treated rats was similar to that of the controls, whereas the diabetic controls failed to thrive. In addition, all of the diabetic controls developed cataracts 1 mo after diabetes induction, whereas none of the treated rats developed cataracts.

Animals↗
PubMed1985

Evidence of random structural features in the heparin polymer.

The first use of computer-simulation studies to examine heparin's structure has been reported. The product distributions obtained when porcine mucosal heparins were depolymerized with heparinase have been compared to computer-simulated distributions. The modeled distribution was relatively unaffected by the polydispersity and molecular weight of heparin. However, the percent of heparinase-cleavable glycosidic linkages and their distribution throughout the polymer resulted in a marked change in the simulated product distribution. The similarity between experimentally observed and computer-simulated product distributions is consistent with the random distribution of heparinase-cleavable sites in porcine mucosal heparin. Finally, a random distribution of N-acetyl residues with respect to heparinase-cleavable sites was experimentally observed.

Animals↗
PubMed1985

Enzymatic removal of bilirubin from blood: a potential treatment for neonatal jaundice.

Current treatments for severe jaundice can result in major complications. Neonatal jaundice is caused by excessive accumulation of bilirubin in the blood. A small blood filter containing immobilized bilirubin oxidase was developed to reduce serum bilirubin concentrations. When human or rat blood was passed through the enzyme filter, more than 90 percent of the bilirubin was degraded in a single pass. This procedure may have important applications in the clinical treatment of neonatal jaundice.

Animals↗
PubMed1985

pH-dependent binding analysis, a new and rapid method for isoelectric point estimation.

Based upon the pH-dependent binding affinity of amphoteric molecules for an ion exchanger, and by taking advantage of batch procedures, a facile method was developed for estimating isoelectric points of these molecules. The new method allows pI measurements to be accomplished within 1 h. Moreover, any possible protein-ampholyte interaction or artifact formation, as may be introduced from the presence of carrier ampholytes when conventional focusing methods are employed, is eliminated by the method. In addition, because of the short processing time, isoelectric points of proteins can be measured at any desired temperature without much risk of protein denaturation. Seven proteins with well-defined isoelectric points were examined by the method. The measured pI values were within a range of 0.2 pH unit or less of the reported values. The precision of pI measurements by the method can be even further improved with the employment of a narrower pH gradient. Since the isoelectric point is an important parameter which governs much of the art of separating proteins, the advent of a simple and rapid method for its measurement would be of use for selecting the proper strategy for protein isolation and purification.

Binding Sites↗
PubMed1985

Inhibition of calcification of bioprosthetic heart valves by local controlled-release diphosphonate.

Bioprostheses fabricated from porcine aortic valves are widely used to replace diseased heart valves. Calcification is the principal cause of the clinical failure of these devices. In the present study, inhibition of the calcification of bioprosthetic heart valve cusps implanted subcutaneously in rats was achieved through the adjacent implantation of controlled-release matrices containing the anticalcification agent ethanehydroxydiphosphonate dispersed in a copolymer of ethylene-vinyl acetate. Prevention of calcification was virtually complete, without the adverse effects of retarded bone and somatic growth that accompany systemic administration of ethanehydroxydiphosphonate.

Animals↗
PubMed1985

Purification and characterization of heparinase from Flavobacterium heparinum.

Heparinase (EC 4.2.2.7) isolated from Flavobacterium heparinum was purified to homogeneity by a combination of hydroxylapatite chromatography, repeated gel filtration chromatography, and chromatofocusing. Homogeneity was established by the presence of a single band on both sodium dodecyl sulfate and acid-urea gel electrophoretic systems. Amino acid analysis shows that the enzyme contains relatively high amounts of lysine residues (9%) consistent with its cationic nature (pI 8.5) but contains only 4 cysteine residues/polypeptide. The molecular weight of heparinase was estimated to be 42,900 +/- 1,000 daltons by gel filtration and 42,700 +/- 1,200 daltons by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The enzyme is very specific, acting only on heparin and heparan monosulfate out of 12 similar polysaccharide substrates tested. It has an activity maximum at pH 6.5 and 0.1 M NaCl and a stability maximum at pH 7.0 and 0.15 M NaCl. The Arrhenius activation energy was found to be 6.3 kcal/mol. However, the enzyme is very sensitive to thermal denaturation and loses activity very rapidly at temperatures over 40 degrees C. Kinetic studies of the heparinase reaction at 37 degrees C gave a Km of 8.04 X 10(-6) M and a Vm of 9.85 X 10(-5) M/min at a protein concentration of 0.5 microgram/ml. By adapting batch procedures of hydroxylapatite and QAE (quaternary aminoethyl)-Sephadex chromatography, gram quantities of heparinase that is nearly free of catalytic enzyme contaminants can be purified in 4-5 h.

Amino Acids↗
PubMed1985

Regulation of drug release from polymer matrices by oscillating magnetic fields.

The reproducible regulation of release of a macromolecule (bovine serum albumin) from biocompatible polymer systems has been demonstrated. Small magnetic spheres or cylindrical magnets were embedded within the polymer matrix which was then subjected to an oscillating magnetic field. In this fashion baseline release rates could be increased 5- to 10-fold with 5-10% standard error. Parameters critical to the regulation of this release included the position, orientation, and magnetic strength of the embedded objects and the amplitude and frequency of the applied magnetic field. Scanning electronmicrographs of the polymer matrix surface reveal that a gap, approximately 100/microns wide, is formed between the embedded object and adjacent polymer material after repeated exposure to an oscillating magnetic field.

Biocompatible Materials↗
PubMed1985

Polymers for the controlled release of macromolecules: effect of molecular weight of ethylene-vinyl acetate copolymer.

Matrices composed of ethylene-vinyl acetate copolymer (EVAc) have been used for controlled delivery of macromolecular bioactive agents. Three EVAc samples of different molecular weight (MW) were selected from solution fractionated samples. The polymer MW is a sensitive factor in affecting the release rate of bovine serum albumin (BSA); the higher the MW of EVAc, the slower the release rate. Depending on the degree of hydrophilicity of the device, the relatively hydrophilic drug particles would cause various degrees of swelling pressure upon water uptake. The relatively hydrophobic EVAc carrier would impose different degrees of restrictive force as determined by polymer MW. The interaction between the restrictive force of the carrier and the swelling pressure of the drug particles is a key factor in affecting the drug release kinetics. As a result, the selection of the polymer carrier can be used to affect the kinetics of a controlled release device.

Animals↗
PubMed1985

Bioerodible polyanhydrides as drug-carrier matrices. I: Characterization, degradation, and release characteristics.

Polyanhydrides based on a variety of aromatic and aliphatic dicarboxylic acids were developed as bioerodible carrier matrices for controlled delivery applications. The high hydrolytic reactivity of the anhydride linkage provides an intrinsic advantage over other classes of bioerodible polymers in versatility and control of degradation rates. For example, using the poly[bis(p-carboxyphenoxy) alkane anhydrides] as models, polymers with degradation rates in the range of 10(-1) to 10(-4) mg/h/cm2 were obtained by changing the alkane from a methyl to a hexyl group. The polymers were characterized by infrared (IR), differential scanning calorimetry, gel permeation chromatography, and scanning electron microscopy (SEM). Near zero-order degradation kinetics were observed for the hydrophobic polyanhydrides over several months. The drug release profile of the model drug p-nitroaniline followed closely that of the degradation of injection-molded poly[bis(p-carboxyphenoxy) propane anhydride] over a period of more than 8 months. Close correlation of polymer degradation and drug release was also observed in other injection-molded samples (10% loading), suggesting a release mechanism that was dominantly degradation controlled. Degradation of these polyanhydrides was pH sensitive, being enhanced in high pH, and became more stable in acidic conditions.

Anhydrides↗
PubMed1985

Does the carrier of chromaffin granules transport the protonated or the uncharged species of catecholamines?

By osmotic lysis in the presence of urea ghosts (60-100 nmol catecholamine/mg prot.) were prepared from chromaffin granules (4-6 mumol catecholamine/mg prot.) of the bovine medulla. In the presence of 1-300 mumol/l 3H-catecholamine and ATP-Mg2+, ghosts show a net uptake of catecholamine. The net uptake is sensitive to reserpine or agents (uncouplers and ammonium) which diminish the electrochemical potential difference for protons at the granule membrane (delta p). The same uptake was found by 3H-counting or by fluorimetric measurements. At various pH-values (pH 6.2-8.2) the Km and Vmax of the ATP-stimulated rate of uptake of 3H-catecholamine into ghosts was determined (at 30 degrees C) to identify the species of catecholamine (protonated, uncharged, or anionic) which is the substrate for the granule carrier. The pH difference (delta pH = pHout - pHin) and the electrical potential difference (delta psi) were determined to calculate delta p under conditions of 3H-catecholamine uptake. When the pHout was increased (pH 6.2, 7.4, 8.2), the apparent Km of uptake decreased (50, 5, 1-2 mumol/l), showing a linear relation between pH and logarithm of Km. The Km was calculated for the uncharged catecholamine (with pK1 = 8.8 and pK2 = 10.0); it was nearly pH-independent and amounted to about 0.2 mumol/l. The Vmax declined only in the extreme pH-range. Between pH 6.6 and 7.8 Vmax and delta p showed a slight increase from 16 to 20 nmoles/(mg prot. X min) and from 110 to 140 mV, resp. In the same pH-range the pHin inside ghosts increased from pH 5.2 to 5.7, whereas delta psi was constant (30 mV). At constant pHout (= 7.3) ammonium (0-30 mmol/l) caused an increase of pHin from 5.5 to 6.6. The increase of pHin was accompanied by an increase of Km from 5 to 20 mumol/l 3H-catecholamine and by a decrease of both Vmax and delta p from 20 to 5 nmoles/(mg prot. X min) and from 123 to 85 mV, respectively. From the dependence of the Km of uptake on pHout is concluded that the uncharged species of catecholamine is transported, whereas the dependence of Km on pHin suggests that the translocation of the catecholamine-carrier complex across the granule membrane is not the rate-limiting step of catecholamine uptake.

Adenosine Triphosphate↗
PubMed1985

The role of polymer matrix structure and interparticle interactions in diffusion-limited drug release.

A lattice random-walk model is used to simulate diffusion in a porous polymer. This model may be useful for the practical design of drug-release systems. Both interacting and noninteracting particles (random walkers) were allowed to diffuse through a pore with a single exit hole. It was found that the specific interactions among the diffusing particles have little influence on the overall release rate. Diffusion through more complicated structures was investigated by simulating the diffusion of particles through two pores connected by a constricted channel whose length and width were varied. The overall rate of release was found to be proportional to the width of the constricted channel. When the length of the channel was greater than or equal to the length of the pore, the rate of release was also inversely proportional to the channel length. From a practical standpoint, release rates can be decreased (and times for release increased) by one or two orders of magnitude by decreasing the width and expanding the length of the interconnecting channels in the polymer matrix.

Delayed-Action Preparations↗