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PubMed1980

Purification and characterization of polyethylene glycol dehydrogenase involved in the bacterial metabolism of polyethylene glycol.

Polyethylene glycol (PEG) dehydrogenase in crude extracts of a PEG 20,000-utilizing mixed culture was purified 24 times by precipitation with ammonium sulfate, solubilization with laurylbetaine, and chromatography with diethylamino-ethyl-cellulose, hydroxylapatite, and Sephadex G-200. The purified enzyme was confirmed to be homogeneous by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The molecular weight of the enzyme, which appeared to consist of four identical subunits, was 2.4 X 10(5). The enzyme was stable below 35 degrees C and in the pH range of 7.5 to 9.0. The optimum pH and temperature of the activity were around 8.0 and 60 degrees C, respectively. The enzyme did not require any metal ions for activity and oxidized various kinds of PEGs, among which PEG 6,000 was the most active substrate. The apparent Km values for tetraethylene glycol and PEG 6,000 were about 10.0 and 3.0 mM, respectively.

Alcohol Oxidoreductases↗
PubMed1983

Antibodies against polyethylene glycol produced in animals by immunization with monomethoxy polyethylene glycol modified proteins.

Antibodies to polyethylene glycol (PEG) were raised in rabbits by immunization with monomethoxy polyethylene glycol modified ovalbumin (OA), bovine superoxide dismutase (SOD), and ragweed pollen extract (Rag), given in Freund's complete adjuvant (FCA). Immunogenicity depended on the nature of the protein and the degree of modification. With modified OA, in the presence of FCA, the majority of animals showed an anti-PEG response. With modified SOD and Rag only a small proportion of animals responded. In the absence of FCA, modified OA, given s.c., did not elicit any anti-PEG antibody response in rabbits and only a weak response in mice. PEG of MW 10,000 and 100,000 given in FCA was found nonimmunogenic in rabbits, and PEG of MW 5.9 X 10(6), given s.c. to mice, showed no or very poor immunogenic properties. Gel diffusion, heterologous passive anaphylaxis and passive hemagglutination were used to demonstrate anti-PEG antibodies raised to PEG-modified proteins. Specificity was confirmed by hapten inhibition of precipitation, inhibition of passive hemagglutination and cross-reactivity tests. PEG of MW greater than or equal to 4,000 produced specific precipitates, smaller molecules acted as monovalent haptens. From hapten inhibition of precipitation by PEG of MW 300 it appears that the antigenic determinant of PEG may be a sequence of 6-7 -CH2CH2O-units. Anti-PEG antibodies can be used analytically. By gel diffusion, Peg was detected in minimal concentrations of 0.1-1 microgram/ml. The clinical relevance of these findings with regard to therapy with PEG-modified enzymes and allergens in humans remains to be established.

Animals↗
PubMed1984

Polyethylene glycol reactive antibodies in man: titer distribution in allergic patients treated with monomethoxy polyethylene glycol modified allergens or placebo, and in healthy blood donors.

Antibodies to polyethylene glycol (PEG) were analyzed in patients with various allergies and in healthy blood donors employing passive hemagglutination. In untreated allergic patients and in healthy blood donors, naturally occurring anti-PEG antibody titers between 32 and 512 were seen in 3.3 and 0.2%, respectively. During hyposensitization with monomethoxy polyethylene glycol modified ragweed extract and honey bee venom, respectively, the patients showed an anti-PEG antibody response. Titers of 32-512 were found in 50% of the patients directly after the first treatment course. After 2 years of treatment the percentage of patients with such titers declined to 28.5%. Mercaptoethanol treatment of sera indicated that the anti-PEG antibodies predominantly were of the IgM isotype. The weak IgM response found in treated patients is considered to be of no clinical significance.

Allergens↗
PubMed1994

Poly-DL-lactic acid: polyethylene glycol block copolymers. The influence of polyethylene glycol on the degradation of poly-DL-lactic acid.

ABA block copolymers of polyethylene glycol and poly-DL-lactic acid were prepared by ring-opening polymerization of DL-dilactide with alpha,omega-dihydroxy polyethylene glycol, Mn 1000 or 2000. The morphology of the resulting copolymers, with PEG:PLA ratios(mol/mol) of 1:2, 1:3 and 1:4, was characterized by DSC and ESR spectroscopy. The rate of water uptake was biphasic, reflecting the contribution of two processes: rapid diffusion of water into the initially miscible PEG and PLA blocks; then a slower rate of hydration possibly due to phase separation and hydrolytic cleavage of the PLA blocks. The rate of hydrolytic degradation of the block copolymers in DI water at 37 degrees C was measured by two methods: weight loss and colorimetric analysis of the carboxy end group concentration resulting from chain scission of PLA blocks. As a result of phase separation, the rate of scission of PLA blocks in the copolymers was similar to that of the PLA homopolymer. The more rapid onset of weight loss of the copolymers, relative to PLA, is attributed to the greater water solubility of PEG-PLA oligomers and their greater diffusivity in the more highly hydrated copolymers.

Biocompatible Materials↗
PubMed2002

An in vitro examination of the impact of polyethylene glycol 400, Pluronic P85, and vitamin E d-alpha-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine.

The potential inhibitory effects of 3 excipients (polyethylene glycol [PEG] 400, Pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate [TPGS]) on the P-glycoprotein (P-gp) -mediated efflux of digoxin (DIG) and cytochrome P450 3A (CYP3A) -mediated metabolism of verapamil (VRP) have been examined in an in vitro permeability model. Experiments were conducted utilizing rat jejunal tissue mounted in diffusion chambers and included assessment of the serosal to mucosal (s to m) transport of DIG and the formation of norverapamil (NOR) during the mucosal to serosal transport of VRP, as measures of P-gp efflux and CYP3A metabolism, respectively. The presence of PEG at 1%, 5%, and 20% (wt/vol) reduced both the s to m flux of DIG (by 47%, 57%, and 64%, respectively, when compared to control) and the metabolism of VRP (by 54%, 78%, and 100%) in a concentration-dependent manner. P85 (0.1% wt/vol) significantly reduced s to m DIG flux by 47% and inhibited VRP metabolism by 42%. TPGS had insignificant effects on both metabolism and efflux at a concentration of 0.01% (wt/vol). The P-gp inhibitory effects of PEG and P85 were evident regardless of whether the excipient was added to the mucosal side, the serosal side, or both sides of the tissue. The current data suggest that inclusion of PEG and P85 as solubilizing agents during in vitro permeability assessment may have a significant impact on both drug metabolism and efflux processes. These compounds appear to exert their effects on P-gp primarily via direct transporter inhibition - or indirectly, through effects on buffer osmolarity, membrane fluidity, and/or mitochondrial toxicity and subsequent adenosine triphosphate (ATP) depletion.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

Comparative acute and subchronic toxicity of ethylene glycol monopropyl ether and ethylene glycol monopropyl ether acetate.

The acute toxicity of ethylene glycol monopropyl ether (EGPE) and ethylene glycol monopropyl ether acetate (EGPEA) was determined in a series of standardized tests. The oral LD50 in rats was 3089 and 9456 mg/kg EGPE and EGPEA, respectively. Skin irritation was slight following an occluded single dose application of either compound to the guinea pig abdomen. The dermal LD50 for guinea pigs was 1 to 5 mL/kg and greater than 20 mL/kg EGPE and EGPEA, respectively. EGPE produced a very weak positive sensitization response in one of five guinea pigs. No positive response was elicited when 10 guinea pigs were similarly challenged with EGPEA. EGPE produced transient moderate to severe eye irritation in rabbits while EGPEA produced slight eye irritation. Subchronic toxicity was determined in a series of oral and inhalation studies. Groups of 10 male rats were dosed with 15, 7.5, 3.75 or 1.88 mmole/kg EGPE and 30, 15 or 7.5 mmole/kg EGPEA by gavage 5 days/week for 6 weeks. Hemoglobinuria was seen at least once at all dose levels of both compounds. EGPE had little effect on feed consumption or body weight gain, while body weight gain was reduced in the two high dose groups exposed to EGPEA and feed consumption was reduced at all dose levels. Hematologic changes were seen at all dose levels of both compounds. Absolute and/or relative spleen weights were increased at all but the lowest EGPE dose level and at all EGPEA dose levels. Gross and histopathologic examinations revealed significant effects on the spleen of animals exposed to EGPE and on the spleen, liver, kidney and testes of animals exposed to EGPEA. The no-observed effect level (NOEL) for splenic changes was 1.88 mmole/kg EGPE. A NOEL for hematology was not established. The NOEL for liver and testicular changes were 15 and 7.5 mmole/kg EGPEA, respectively while a NOEL for hematologic, splenic and renal changes was not established. Groups of 10 rats (5M, 5F) were exposed to 800, 400, 200 or 100 ppm EGPE or EGPEA 6 hr/day, 5 days/week for a total of 11 exposures. Body weight gains in all exposure groups were comparable to controls. Hemoglobinuria was seen only after the first or second exposure in males and females exposed to 800 ppm EGPE and in males exposed to 400 ppm EGPE. Males and females exposed to 800 ppm EGPEA and females exposed to 400 and 200 ppm EGPEA also exhibited hemoglobinuria.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Topical↗
PubMed1984

Ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate teratology studies.

An inhalation teratology study was conducted in rats at 10, 50 and 250 ppm ethylene glycol monoethyl ether (EGEE) and in rabbits at 10, 50 and 175 ppm EGEE. This study was designed to supplement a study conducted for NIOSH which showed teratogenic effects in rats at 200 ppm EGEE and in rabbits at about 160 ppm EE. In this study, EGEE was found not to cause teratogenic effects at concentrations up to and including 250 ppm in rats and 50 ppm in rabbits, while 175 ppm EGEE was considered to be a marginal effect level for teratogenic effects in rabbits. Fetotoxicity was observed at 250 ppm EGEE and possibly at 50 ppm EGEE in rats. An inhalation teratology study using ethylene glycol monoethyl ether acetate (EGEEA) has been conducted in rabbits at 25, 100 and 400 ppm. There was evidence of teratogenicity (vertebral malformations) at 400 ppm EGEEA and slight fetotoxicity at 100 ppm; 25 ppm was a no effect level.

Abnormalities, Drug-Induced↗
PubMed1987

Field study of the urinary excretion of ethoxyacetic acid during repeated daily exposure to the ethyl ether of ethylene glycol and the ethyl ether of ethylene glycol acetate.

The urinary excretion of ethoxyacetic acid (EAA) was studied in a group of five women daily exposed to the ethyl ether of ethylene glycol (EGEE) and the ethyl ether of ethylene glycol acetate (EGEE-Ac) during 5 d of normal production and 7 d after a 12-d production stop. The mean combined exposure concentration of EGEE and EGEE-Ac (expressed in equivalent weight of EGEE) was 14.0 mg/m3 with occasional slight excursions above the current Belgian occupational exposure limit. The daily combined exposure profiles for EGEE and EGEE-Ac were rather constant during the first observation period, but they tended to decrease during the last week. The urinary EAA excretion clearly increased during the work week. Over the weekends the elimination was far from complete, and even after a prolonged nonexposure period of 12 d traces of the metabolite were still detectable. Based on the observations from the first period, a good linear correlation (r = 0.92) was found between the average exposure over 5 d (14.4 mg/m3) and the EAA excretion at the end of the week (105.7 mg/g creatinine). An EAA estimate of 150 +/- 35 mg/g was found to correspond with repeated 5-d full-shift exposures to the respective occupational exposure limit of EGEE (19 mg/m3) or EGEE-Ac (27 mg/m3).

Acetates↗
PubMed2001

Protein release microparticles based on the blend of poly(D,L-lactic-co-glycolic acid) and oligo-ethylene glycol grafted poly(L-lactide).

Bovine serum albumin (BSA), a model protein drug, was encapsulated with a microparticle based on the blend of poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(L-lactide)-g-oligo(ethylene glycol) (PLLA-g-oligoEG). Effects of PLLA-g-oligoEG in the blend on degradation, characteristic properties, and release behavior of the microparticle were studied. Drug loading efficiency increased with increase in the graft frequency of oligoEG in the graft copolymer in the blend. The release of BSA was found to be more efficient for microparticles based on the blend than on the PLGA, which is due to the faster protein diffusion through the swollen phase of the hydrogel-like structure. The microparticles based on the blend showed a slower degradation and a lower pH shift compared to that of PLGA.

Calorimetry, Differential Scanning↗
PubMed1996

Purification of a mammalian homologue of Escherichia coli endonuclease III: identification of a bovine pyrimidine hydrate-thymine glycol DNAse/AP lyase by irreversible cross linking to a thymine glycol-containing oligoxynucleotide.

We purified a homologue of the Escherichia coli DNA repair enzyme endo nuclease III 5000-fold from calf thymus which, like endonuclease III, demonstrates DNA-glycosylase activity against pyrimidine hydrates and thymine glycol and AP lyase activity (DNA strand cleavage at AP sites via beta-elimination). The functional similarity between the enzymes suggested a strategy for definitive identification of the bovine protein based on the nature of its enzyme-substrate (ES) intermediate. Prokaryotic DNA glycosylase/AP lyases function through N-acylimine (Schiff's base) ES intermediates which, upon chemical reduction to stable secondary amines, irreversibly cross link the enzyme to oligodeoxynucleotides containing substrate modified bases. We incubated endonuclease III with a 32P- labeled thymine glycol-containing oligodeoxynucleotide in the presence of NaCNBH3. This resulted in an increase in the apparent molecular weight of the enzyme by SDS-PAGE. Phosphorimaging confirmed irreversible cross linking between enzyme and DNA. Identical treatment of the most purified bovine enzyme fraction resulted in irreversible cross linking of the oligodeoxynucleotide to a predominant 31 kDa species. Amino acid analysis of the 31 kDa species revealed homology to the predicted amino acid sequence of a Caenorhabditis elegans 27.8 kDa protein which, in turn, has homology to endonuclease III. The translated amino acid sequences of two partial 3' cDNAs, from Homo sapiens and Rattus sp., also demonstrate homology to the C. elegans and bovine sequences suggesting a homologous family of endonuclease III-like DNA repair enzymes is present throughout phylogeny.

Amino Acid Sequence↗
PubMed1998

Uracil glycol deoxynucleoside triphosphate is a better substrate for DNA polymerase I Klenow fragment than thymine glycol deoxynucleoside triphosphate.

A major stable oxidation product of DNA cytosine is 5,6-dihydroxy-5, 6-dihydrouracil (Ug). Ug can be formed directly in DNA or in the cellular nucleotide pools by deamination of the unstable primary product, cytosine glycol. Here, we synthesized dUgTP and showed that dUgTP was incorporated in place of dTTP and was a much better substrate for the model enzyme DNA polymerase I Klenow fragment lacking proofreading activity, Kf (exo-), than deoxythymidine glycol triphosphate (dTgTP). The relative efficiency for dUgTP insertion opposite A was 10 times higher than for dTgTP; however, the extension of a primer with 3' dUg was about 100 times more efficient than the extension of a primer with 3' dTg. At the insertion step, the differences in Vmax appeared to be responsible since the apparent Kms for dUgTP and dTgTP were about the same. In contrast, both the apparent Km and Vmax for elongation of dUg were markedly different from those of dTg. Molecular modeling was performed with both Tg and Ug and provides a rational structural explanation for these observations.

Cytosine↗
PubMed2003

Preparation of discrete oligoethers: synthesis of pentabutylene glycol and hexapropylene glycol by two complementary methods.

Two experimentally facile methods for the preparation of discrete oligoethers are reported. The first involves an iterative sequence of oxidation, acetal formation, and reductive ring opening for the synthesis of penta-1,4-butylene glycol. The second method is also iterative, comprising phase-transfer etherification and end-group deprotection to form hexa-1,3-propylene glycol. These methods offer significantly improved yields and purification protocols over previously reported syntheses.

Journal Article↗
PubMed1993

Oxidative damage to DNA: levels of thymine glycol and thymidine glycol in neoplastic human urines.

We have measured the levels of thymine glycol (TG) and thymidine glycol (dTG) in human urine, using an HPLC method. The results show that all 30 specimens examined (including 10 non-neoplastic and 20 neoplastic human urines) contained significant amounts of TG and dTG, average levels (mean +/- SEM) were 0.376 +/- 0.026 and 0.138 +/- 0.009 nmol/kg body weight/day respectively. The average levels of TG and dTG were 0.435 +/- 0.038 and 0.164 +/- 0.017 nmol/kg body weight/day in 10 healthy human urine specimens and 0.347 +/- 0.035 and 0.125 +/- 0.010 nmol/kg body weight/day in 20 neoplastic human urine specimens respectively. No significant differences were found between female and male as well as between the non-neoplastic and neoplastic human urine specimens. There were also wide interindividual variations, which were not age-dependent.

Adolescent↗
PubMed1983

Comparative aspects of the reproductive toxicology by inhalation in rats of ethylene glycol monomethyl ether and propylene glycol monomethyl ether.

This study was designed to provide a rapid assessment of the effect of two glycol ethers on some aspects of reproduction in the rat. Exposure was by inhalation at 100 and 300 ppm (EGME) and 200 and 600 ppm (PGME) for 6 hr/day. The study was in two parts: (a) Pregnant females were exposed on Days 6 to 17 of gestation. Body weight gain was reduced in both EGME groups. No litters were delivered in the 300-ppm EGME group and only 9/20 rats in the 100-ppm EGME group produced litters where the number, weight, and viability of the pups were reduced, but the pups appeared normal externally. Exposure at 200 and 600 ppm PGME had no effect. (b) Male rats were exposed for 10 days. There was a reduction in testicular weight accompanied by semeniferous tubular atrophy in the 300-ppm EGME group. There were no effects at 100 ppm EGME or 200 and 600 ppm PGME. 300 ppm EGME caused significant reductions in white blood cell count, red blood cell count, hemoglobin concentration, hematocrit, and mean cell hemoglobin. The study design proved capable of demonstrating the effects of EGME on the testes and on fetal development and highlighted PGMEs lack of activity at the doses tested.

Animals↗
PubMed1990

Heat sterilization of bioindicators in propylene glycol and propylene glycol-water mixtures: arrhenius equation, thermodynamic data, and Z values.

Our interest in calculating the thermodynamic data by means of the Arrhenius equation was based on two observation: (a) the thermal death time increases considerably when the bioindicators Bacillus subtilis var. niger and Bacillus stearothermophilus are sterilized in nonaqueous hydrophilic solutions as found in propylene glycol (PG) with low water concentrations; and (b) the inactivation kinetics of Bac. stearothermophilus does not follow a first-order reaction. The frequency factor A and the entropy of activation delta S* have the highest values in water and the lowest value in PG; delta S* for Bac. stearothermophilus in water is 812 J/mol K; however, in PG it is -9.6 J/mol K. A good correlation between delta S* and the enthalpy delta H* is found, indicating possible protein denaturation during thermal inactivation. The moderate positive and negative delta S* values in PG and PG with low water concentrations might be explained by (a) rigid conformation of proteins due to stabilization and (b) slow reaction, making the complex a less probable structure, when the activated complex is built only under considerable rearrangement of the structure of the reactant molecules. The opposite was observed with the Z and Z* values, the latter being defined as Z values of nonlogarithmic survival curves. The Z values increase with increasing concentrations of PG, i.e., for Bac. subtilis of Z = 8 degrees C in water up to Z = 23 degrees C in PG and for Bac. stearothermophilus of Z = 6 degrees C up to Z* = 27 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacillus subtilis↗
PubMed1992

Osmolalities of propylene glycol-containing drug formulations for parenteral use. Should propylene glycol be used as a solvent?

Propylene glycol (PG) is a widely used vehicle for water-insoluble drugs. Injection of drugs formulated with this solvent often results in pain, thrombosis, or thrombophlebitis that can be reduced by premedication with local anesthetics or opioids. Because osmolality and pH that are unphysiologic may cause these adverse effects, we assessed the contribution of PG to the osmolality of parenteral drug formulations. Osmolality of PG measured in distilled water showed that PG content and osmolality were directly related: 2% wt/vol PG, 264 mOsm/L; 100% PG, 15, 200 mOsm/L. The osmolalities of commercially available preparations of drugs dissolved in PG ranged from 365 mOsm/L (2% PG content) to 12,800 mOsm/L (83.46% PG), with most above 1000 mOsm/L. Replacement of PG by a solvent with lower osmolality in Germany has effectively reduced the incidence of side effects for one drug. Until PG can be replaced in drugs, we recommend diluting drugs in a large volume of saline solution; this may help to minimize the undesirable effects of this solvent.

Anesthesiology↗
PubMed1984

Effects of oxytetracycline in propylene glycol, oxytetracycline in saline solution, and propylene glycol alone on blood ionized calcium and plasma total calcium in sheep.

Intravenous injection of oxytetracycline HC1 (OTC) in propylene glycol (PG), OTC in saline solution, and PG alone in sheep had no significant (P less than 0.01) effects on total plasma calcium concentrations over a 60-minute period. In contrast, ionized calcium concentrations in whole blood were significantly (P less than 0.01) depressed for approximately 3 minutes after OTC in PG and OTC in saline solution, IV. A slight depression of ionized calcium concentrations was noticed after injection of PG alone. Seemingly, calcium chelation by OTC may be a major factor in the collapse syndrome of ungulates given preparations containing OTC by rapid IV injection.

Animals↗
PubMed2000

Development and in vitro characterization of vascular endothelial growth factor (VEGF)-loaded poly(DL-lactic-co-glycolic acid)/poly(ethylene glycol) microspheres using a solid encapsulation/single emulsion/solvent extraction technique.

Poly(DL-lactide-co-glycolide) (PLGA)/polyethylene glycol (PEG) microspheres are one modality of controlled delivery of biologically active molecules that would further the development of engineered tissues. As a possible mechanism to stimulate angiogenesis within an engineered tissue, vascular endothelial growth factor (VEGF) and bovine serum albumin (BSA) were coencapsulated into microspheres fabricated from PEG and 50/50 PLGA using a solid-encapsulation/single-emulsion/solvent extraction technique. Two VEGF/BSA ratios were studied: 1:2000 and 1:10,000. Analysis consisted of the loading efficiency, particle size distribution, bright-field microscopy, scanning electron microscopy, release kinetics, and an in vitro human umbilical vein endothelial cell proliferation assay to assess biological activity of the released VEGF. Results show the microspheres could be manufactured, stored, and degraded over 28 days. The burst release rates for 1:2000 and 1:10,000 VEGF/BSA microspheres were 71.87 +/- 8.11 and 27.91 +/- 1.71 ng/mL (mean +/- standard error of the mean), respectively; steady-state release rates were 6.56 +/- 1.10 and 2.21 +/- 0.47 ng/mL, respectively. The microspheres released biologically active VEGF, and the VEGF increased the proliferation of HUVECs in culture (p <.05). The successful development of a novel, cost-effective, scalable technique for producing microspheres loaded with biologically active proteins is presented. Using the data obtained from these studies, a defined concentration of microspheres will deliver a quantifiable level of VEGF at a known release rate.

Animals↗