An experimental study for syndiotactic polyvinyl alcohol spheres as an embolic agent: can it maintain spherical shape in vivo?

Syndiotactic polyvinyl alcohol (PVA) had been developed to overcome the drawbacks of atactic PVA spheres that deform easily, which can lead to non-target embolization. This study was performed to evaluate the in vivo stability of spherical shape of the syndiotactic PVA spheres. Selective arteriography and transarterial embolization (TAE) were performed in the main renal arteries of eight New Zealand white rabbits using syndiotactic PVA sphere that consisted of syndiotactic PVA skin and a copolymer core of vinyl acetate/vinyl pivalate. The size of the syndiotactic PVA spheres used for the TAE was 212-355 µm. The rabbits were sacrificed 12-14 days after TAE. Gross and microscopic examinations of each kidney were performed. The microscopic examination showed infarction of all embolized kidneys. Syndiotactic PVA spheres were seen uniformly within the arterial lumen and appeared as round ring-like structures without any deformity. The syndiotactic PVA spheres exclusively occupied the arterial lumen. As a conclusion, syndiotactic PVA spheres maintained their spherical shape without significant deformation in this in vivo short-term experimental study. Further investigation is necessary for evaluation of detailed effects of physical stability in tumor embolization.

Synthesis and characterization of a polyacetylene derivative with phenylazobenzene moieties.

A new polyacetylene derivative was prepared by the activated polymerization of 2-ethynylpyridine by using 4-(phenylazo)benzoyl chloride without any additional initiator or catalyst in high yield. The chemical structure of poly[2-ethynyl-N-(4-(phenylazo)benzoyl) pyridinium chloride [PEPABPC] was characterized by such instrumental methods as NMR, IR, and UV-visible spectroscopies to have a conjugated polymer backbone system with the designed azobenzene moieties. The electrooptical and electrochemical properties of PEPABPC were studied. The photoluminescence spectrum showed that the PL peak is at 597 nm corresponding to the photon energy of 2.07 eV. The cyclovoltammograms of PEPABPC exhibited the irreversible electrochemical behaviors between the oxidation and reduction peaks. The oxidation current density of PEPABPC versus the scan rates is approximately linear relationship in the range of 30 mV/sec-150 mV/sec. It was found that the the kinetics of the redox process of this polymer is controlled by the reactant diffusion process from the oxidation current density of PEPABPC versus the scan rates.

Synthesis and properties of poly(4-vinylpyridine-co-styrene) with pendant azobenzonitrile moieties.

A new ionic polymer, poly(4-vinylpyridine-co-styrene) [PVPS] with pendant azobenzonitrile moieties was prepared by the polymeric reaction of PVPS and 4-[4-(8-bromooctyloxy)phenylazo]benzonitrile. The polymer structure was characterized by various instrumental methods to have a PVPS backbone system with the designed azobenzonitrile moieties. The electrochemical and electro-optical properties were studied. The polymer showed two oxidation and reduction response properties in a polymer unit and two electrochemical processes were included in the irreversible redox steps. The plot of the oxidation current density of polymer versus the scan rate showed approximately a linear relationship in the range of 30 mV/sec 150 mV/sec. The exponent of scan rate, when we apply power law to our data, was found to be 0.35. The absorption spectrum showed a characteristic absorption peak at 365 nm.

Preparation and evaluation of Cremophor-free paclitaxel solid dispersion by a supercritical antisolvent process.

OBJECTIVES: To avoid the major adverse effects induced by Cremophor EL formulated in the commercial paclitaxel products of Taxol. METHODS: An injectable paclitaxel solid dispersion free of Cremophor was prepared by a supercritical antisolvent process and then was fully characterized and investigated with regard to its short-term and long-term stability. Pharmacokinetics in rats was also evaluated compared with the commercial product. KEY FINDINGS: The solid dispersion system at a 1/20/40 weight ratio of paclitaxel/HP-ß-CD/HCO-40 had a paclitaxel solubility of about 10 mg/ml, an almost 10 000-fold increase over its aqueous solubility. This system was physically stable for at least six months or four weeks in accelerated conditions (40 ± 2°C; RH: 75 ± 5%) and stress conditions (60°C), respectively. The precipitation time of paclitaxel solid dispersion in 0.9% sodium chloride injection at a concentration of 1000 µg/ml was above 70 h at room temperature. Intravenous administration of paclitaxel solid dispersion at a dose of 6 mg/kg revealed no significant differences when compared with the commercial product. However, our results obtained at a dose of 12 mg/kg showed a striking non-linear increase in the plasma Cmax and AUCall with increased dose. In addition, the concentrations of paclitaxel in various organs in the solid dispersion group were found to be higher than those of Taxol at 6 mg/kg, and the paclitaxel levels in these organs increased proportionately with increasing dose. CONCLUSIONS: Nano-scale paclitaxel solid dispersion without Cremophor EL provided advantageous results over Taxol with respect to the physicochemical properties, safety, clinic convenience and pharmacokinetic behaviour in rats.

A rapid method to determine tetrabromobisphenol a in rat serum and urine by liquid chromatography-tandem mass spectrometry.

Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame retardants in the world, is used to improve fire safety of laminates in electrical and electronic equipment. A liquid chromatography-tandem mass spectrometry was developed for the determination of TBBPA in rat serum and urine, and applied to the toxicokinetic study of TBBPA in rats. Acceptable linearity was observed over the concentration ranges of 0.25-50 and 0.01-5 µg/mL in serum and urine, respectively. The limits of detection of TBBPA were 0.04 µg/mL in serum, and 0.0025 µg/mL in urine. The precisions for the assay in serum and urine were below 13 and 14%, respectively, and the accuracies ranged 95-111% and 98-101% for intraday and 97-107% and 97-102% for inter-day, respectively. Serum and urine concentrations of TBBPA were successfully monitored following oral administrations at the dose of 200 mg/kg in male Sprague Dawley rats. Toxic signs were not observed at 200 mg/kg of TBBPA. The present results suggest that the rapid method developed in the present study affords sensitivity, accuracy and precision necessary for quantitative measurements in toxicokinetic studies of TBBPA in vivo.

Synthesis and electrostatic nano-assembly of water-soluble polybenzothiadiazole derivatives with long-wavelength emission in the solid states.

We have synthesized APBT and APTBT containing benzothiadiazole units by Suzuki cross-coupling reaction with good yield. The polymers showed blue emission colors in aqueous solutions, while long wavelength shift was observed in the solid state due to facilitated exciton migration. APBT and APTBT are water-soluble and highly-fluorescent conjugated polymers with negatively charged sulfonate side chains and thus they can be electrostatically assembled with oppositely charged polyelectrolyte such as cationic polymer, poly(dimethyldiallylammonium chloride) (PDAC) via layer-by-layer (LbL) deposition technique on a glass slide. According to the increased the number of bilayer, we found that the assembled film exhibited larger enhancement of the long wavelength emission relative to the blue emission, due to the increased excition migration.

Role of metabolism in 1-bromopropane-induced hepatotoxicity in mice.

A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in male ICR mice. The depletion of glutathione (GSH) by formation of GSH conjugates was associated with increased hepatotoxicity in 1-BP-treated mice. The formation of S-propyl and 2-hydroxypropyl GSH conjugates were identified in the liver following 1-BP treatment. In addition, the formation of reactive metabolites of 1-BP by certain cytochrome P-450 (CYP) may be involved in 1-BP-induced hepatotoxicity. The decreased content of hepatic GSH produced by 1-BP was associated not only with increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but also with elevated levels of hepatic thiobarbituric acid-reactive substance (TBARS) in mice where metabolic enzymes were induced by pretreatment with phenobarbital. In addition, the hepatotoxicity induced by 1-BP was prevented by pretreatment with SKF-525A. Taken together, the formation of reactive metabolites by CYP and depletion of GSH may play important roles in hepatotoxicity induced by 1-BP.

Gentamicin-loaded wound dressing with polyvinyl alcohol/dextran hydrogel: gel characterization and in vivo healing evaluation.

To develop a gentamicin-loaded wound dressing, cross-linked hydrogel films were prepared with polyvinyl alcohol (PVA) and dextran using the freezing-thawing method. Their gel properties such as gel fraction, swelling, water vapor transmission test, morphology, tensile strength, and thermal property were investigated. In vitro protein adsorption test, in vivo wound healing test, and histopathology were performed. Dextran decreased the gel fraction, maximum strength, and thermal stability of hydrogels. However, it increased the swelling ability, water vapor transmission rate, elasticity, porosity, and protein adsorption. The drug gave a little positive effect on the gel properties of hydrogels. The gentamicin-loaded wound dressing composed of 2.5% PVA, 1.13% dextran, and 0.1% drug was more swellable, flexible, and elastic than that with only PVA because of its cross-linking interaction with PVA. In particular, it could provide an adequate level of moisture and build up the exudates on the wound area. From the in vivo wound healing and histological results, this gentamicin-loaded wound dressing enhanced the healing effect more compared to conventional product because of the potential healing effect of gentamicin. Thus, this gentamicin-loaded wound dressing would be used as a potential wound dressing with excellent forming and improved healing effect in wound care.

Gel characterisation and in vivo evaluation of minocycline-loaded wound dressing with enhanced wound healing using polyvinyl alcohol and chitosan.

The purpose of this study was to develop a minocycline-loaded wound dressing with an enhanced healing effect. The cross-linked hydrogel films were prepared with polyvinyl alcohol (PVA) and chitosan using the freeze-thawing method. Their gel properties, in vitro protein adsorption, release, in vivo wound healing effect and histopathology were then evaluated. Chitosan decreased the gel fraction, maximum strength and thermal stability of PVA hydrogel, while it increased the swelling ability, water vapour transmission rate, elasticity and porosity of PVA hydrogel. Incorporation of minocycline (0.25%) did not affect the gel properties, and chitosan hardly affected drug release and protein adsorption. Furthermore, the minocycline-loaded wound dressing composed of 5% PVA, 0.75% chitosan and 0.25% drug was more swellable, flexible and elastic than PVA alone because of relatively weak cross-linking interaction of chitosan with PVA. In wound healing test, this minocycline-loaded PVA-chitosan hydrogel showed faster healing of the wound made in rat dorsum than the conventional product or the control (sterile gauze) due to antifungal activity of chitosan. In particular, from the histological examination, the healing effect of minocycline-loaded hydrogel was greater than that of the drug-loaded hydrogel, indicating the potential healing effect of minocycline. Thus, the minocycline-loaded wound dressing composed of 5% PVA, 0.75% chitosan and 0.25% drug is a potential wound dressing with excellent forming and enhanced wound healing.

Superhydrophobic PLA fabrics prepared by UV photo-grafting of hydrophobic silica particles possessing vinyl groups.

Superhydrophobic poly(lactic acid) (PLA) fabrics are prepared by UV photo-grafting of hydrophobic silica particles possessing vinyl functional groups on the surfaces, which is a novel one-step process to provide surface with roughness as well as hydrophobicity simultaneously. For this purpose, hydrophobic silica particles with vinyl groups and average diameter of 1.51+/-0.05 microm are synthesized via a sol-gel process. The silica particles possessing vinyl groups are found to be effectively immobilized on PLA fabrics via UV photo-grafting reaction. The water contact angle of the treated PLA fabric is measured to be approximately 150 degrees, which is high enough to exhibit the Lotus effect as a result of the superhydrophobicity.

Anti-inflammatory action of mollugin and its synthetic derivatives in HT-29 human colonic epithelial cells is mediated through inhibition of NF-kappaB activation.

Mollugin is the active compound of Rubia cordifolia, which has been used as a traditional Chinese medicine for the treatment of various inflammatory diseases including arthritis and uteritis. In the present study, we investigated for the first time the inhibitory effects and the mechanisms of action of mollugin (M1) and its synthetic derivatives (M2-M4) on tumor necrosis factor (TNF)-alpha-induced inflammatory responses in HT-29 human colon epithelial cells. Treatment with M1 and its derivatives M2-M4 significantly inhibited TNF-alpha-induced attachment of U937 monocytic cells to HT-29 cells, which mimics the initial phase of colon inflammation. TNF-alpha-induced mRNA induction of the chemokines, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8, and the intercellular cell adhesion molecule (ICAM)-1, which are involved in adhesion between leukocytes and epithelial cells, was suppressed by M1-M4, and M1 was the most efficacious. In addition, M1-M4 significantly suppressed TNF-alpha-induced NF-kappaB transcriptional activity. Such NF-kappaB inhibitory activity of M1-M4 (20 microM) correlated with their ability to suppress TNF-alpha-induced chemokine expression and U937 monocytic cell adhesion to HT-29 colonic epithelial cells. Treatment of HT-29 cells with M1 and PDTC, a NF-kappaB inhibitor, synergistically suppressed both TNF-alpha-induced NF-kappaB activation and monocytic cell adhesion to HT-29 cells. These results suggest that M1-M4 inhibit TNF-alpha-induced expression of inflammatory molecules via NF-kappaB, and that M1, a potent NF-kappaB inhibitor, may be a valuable new drug candidate for the treatment of colon inflammation.

Synthesis and photochromic properties of poly(4-vinylpyridine-co-styrene) with pendant spiroxazine moieties.

An ionic polymer with pendant photochromic moieties was prepared by the reaction of poly(4-vinylpyridine-co-styrene) and 1,3,3-trimethyl-6'-bromohexyloxyspiro[2H]-indol-2,3'-[3H]-naphth[2,1-b][1,4]oxazine. The photochromic reaction in question is caused by the reversible heterolytic cleavage of the C(spiro)-O bond under UV irradiation, yielding the colored form that can return to the colorless form by ring closure under visible light irradiation or in dark. The visible range absorption of the corresponding polymer increased gradually by UV irradiation which is ascribed to the generation of the open merocyanine form from the closed spiro form. The ionic conductivity of polymer increased upon UV irradiation, which brought about the generation of zwitterions form, and subsequently decreased in dark, which brought about the generation of closed spiro form. Sufficient reversibility was found in this polymer and this response was completely synchronized with that in the absorbance changes.

Development of clindamycin-loaded wound dressing with polyvinyl alcohol and sodium alginate.

To develop a clindamycin-loaded wound dressing, cross-linked hydrogel films were prepared using freeze-thawing method with various mixtures of polyvinyl alcohol (PVA) and sodium alginate (SA). The physicochemical properties such as swelling ratio, tensile strength and elongation of hydrogels were evaluated. The drug release from this clindamycin-loaded hydrogel, in vitro protein adsorption test and in vivo wound healing observations in rats were then performed. Increased SA concentration decreased the gelation %, maximum strength and break elongation, but it resulted into an increment in the swelling ability, elasticity and thermal stability of hydrogel film. However, SA had insignificant effect on the release of clindamycin. This hydrogel improved the healing rate of artificial wounds in rats. Thus, a clindamycin-loaded wound dressing with PVA and SA hydrogel should be a candidate for wound care.

Preparation and evaluation of fast dissolving ibuprofen-polyethylene glycol 6000 solid dispersions.

To improve its oral absorption, rapidly dissolving ibuprofen solid dispersions (SD) were prepared in a relatively easy, simple, quick, inexpensive, and reproducible manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). They were evaluated for solubility, in vitro release, and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and resolidification as revealed by SEM indicated the formation of effective SDs. Absence or shifting toward the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. However, no such interactions in the solid state were confirmed by FTIR spectra that showed the presence of drug crystalline in SDs. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C(max), and a significant decrease in T(max) over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast-dissolving ibuprofen SDs by low temperature melting method using PEG 6000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution, and absorption rate of ibuprofen.

Preparation and in vivo evaluation of piroxicam-loaded gelatin microcapsule by spray drying technique.

To develop a piroxicam-loaded gelatin microcapsule with enhanced bioavailability, a gelatin microcapsule encapsulated ethanol and piroxicam has been formulated by using gelatin as a water-soluble polymer shell. The aqueous solubility and bioavailability of piroxicam in piroxicam-loaded microcapsule in rats were then evaluated compared to piroxicam powder. The piroxicam-loaded gelatin microcapsule spherical in shape with smooth surface showed the geometric mean diameter of about 19 microm. It had the piroxicam solubility of about 1.87 mg/ml and the amount of ethanol of about 4.37 microg/mg. Furthermore, it gave significantly higher total plasma concentrations, Cmax and area under the blood concentration-time curve (AUC) of piroxicam in rats than did piroxicam powder, indicating that the drug from gelatin microcapsule could be more orally absorbed in rats. In particular, the AUC of piroxicam in gelatin microcapsule was significantly about 2 fold increased compared to piroxicam powder. This enhanced oral relative bioavailability of piroxicam in gelatin microcapsule was contributed by the marked increase in the absorption rate of piroxicam due to the improved solubility of piroxicam. Thus, the piroxicam-loaded gelatin microcapsule developed using spray-drying technique with gelatin, sodium lauryl sulfate and ethanol would be useful to deliver piroxicam in a pattern that allows fast absorption in the initial phase, leading to better absorption.

Gelation-induced fluorescence enhancement of benzoxazole-based organogel and its naked-eye fluoride detection.

The benzoxazole derivative gelator forms a stable DMF/toluene cosolvent gel with dramatically enhanced fluorescence emission compared to its mother solution. The translucent colorless gel was changed to a solution with strong greenish fluorescence in the presence of fluoride anion with disruption of the gel structure.

Development of polyvinyl alcohol-sodium alginate gel-matrix-based wound dressing system containing nitrofurazone.

Polyvinyl alcohol (PVA)/sodium alginate (SA) hydrogel matrix-based wound dressing systems containing nitrofurazone (NFZ), a topical anti-infective drug, were developed using freeze-thawing method. Aqueous solutions of nitrofurazone and PVA/SA mixtures in different weight ratios were mixed homogeneously, placed in petri dishes, freezed at -20 degrees C for 18h and thawed at room temperature for 6h, for three consecutive cycles, and evaluated for swelling ratio, tensile strength, elongation and thermal stability of the hydrogel. Furthermore, the drug release from this nitrofurazone-loaded hydrogel, in vitro protein adsorption test and in vivo wound healing observations in rats were performed. Increased SA concentration decreased the gelation%, maximum strength and break elongation, but it resulted into an increment in the swelling ability, elasticity and thermal stability of hydrogel film. However, SA had insignificant effect on the release of nitrofurazone. The amounts of proteins adsorbed on hydrogel were increased with increasing sodium alginate ratio, indicating the reduced blood compatibility. In vivo experiments showed that this hydrogel improved the healing rate of artificial wounds in rats. Thus, PVA/SA hydrogel matrix based wound dressing systems containing nitrofurazone could be a novel approach in wound care.

Preparation and lead ion removal property of hydroxyapatite/polyacrylamide composite hydrogels.

We report the synthesis of hydroxyapatite/polyacrylamide (HAp/PAAm) composite hydrogels with various HAp contents by free radical polymerization and their removal capability of Pb(2+) ions in aqueous solutions with controlled initial Pb(2+) ion concentrations and pH values of 2-5. The swelling ratio of the composite gels in aqueous solutions decreases with increasing the HAp content in the gels. The composite gel with higher HAp content exhibits the higher removal capacity of Pb(2+) ions owing to the higher adsorption sites for Pb(2+) ions, but shows the slower removal rate of Pb(2+) ions due to the lower degree of swelling. The removal mechanism of Pb(2+) ion is very sensitive to the pH value in aqueous solution, although the removed amount of Pb(2+) ion is nearly same, regardless of pH values of 2-5. The removal mechanism, the dissolution of HAp in the composite gel and subsequent precipitation of hydroxypyromorphite (HPy), is dominant at lower pH 2-3, whereas the mechanism, the adsorption of Pb(2+) ions on the composite gel and following cation exchange reaction between Pb(2+) ions adsorbed and Ca(2+) of HAp, is dominant at higher pH 4-5. The equilibrium removal process of Pb(2+) ions by the composite gels at pH 5 is described well with the Langmuir isotherm model. The equilibrium removal capacities of the composite gels with 30, 50, and 70 wt.% HAp contents are evaluated to be 123, 178, and 209 mg/g, respectively.

Evaluation of skin permeation and accumulation profiles of a highly lipophilic fatty ester.

The aim was to evaluate the skin permeation and accumulation profiles of a highly lipophilic fatty ester using the combination of various permeation enhancing techniques to study the potential of highly lipophilic fatty esters as local topical agents. Permeation and accumulation profiles of ketorolac stearate (C18:0) were studied using solubility improved formulation, supersaturated solution of permeant in enhancer vehicle, lipophilic receptor solution, enhancer pretreatment, and the removal of stratum corneum and delipidization of skins. Impermeability and minimal skin accumulation of ketorolac stearate could delineate a preliminary possibility for designing safer topical agents without systemic absorption.