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At least 145 records · Page 8Linked to original sources
PubMed2005

Galactosylated polyethylenimine-graft-poly(vinyl pyrrolidone) as a hepatocyte-targeting gene carrier.

Polyethylenimine (PEI) has been used for the gene delivery system in vitro and in vivo since it has high transfection efficiency owing to proton buffer capacity. However, the use of PEI for gene delivery is limited due to cytotoxicity, non-specificity and unnecessary interaction with serum components. To overcome cytotoxicity and non-specificity, PEI was coupled with poly(vinyl pyrrolidone) (PVP) as the hydrophilic group to reduce cytotoxicity and lactose bearing galactose group for hepatocyte targeting. The galactosylated-PEI-graft-PVP (GPP) was complexed with DNA, and GPP/DNA complexes were characterized. GPP showed good DNA binding ability, high protection of DNA from nuclease attack. The sizes of DNA complexes show tendency to decrease with an increase of charge ratio and had a minimum value around 59 nm at the charge ratio of 40 for the GPP-1/DNA complex (PVP content: 4.1 mol%). The GPP showed low cytotoxicity. And GPP/DNA complexes were mediated by asialoglycoprotein receptors (ASGP-R)-mediated endocytosis. Also, the transfection efficiency of GPP-1/DNA complex at charge ratio of 40 in the HepG2 was higher than that of PEI/DNA one.

Cell Line, Tumor↗
PubMed2006

Superiority of N-methyl pyrrolidone over albumin with hypericin for fluorescence diagnosis of human bladder cancer cells implanted in the chick chorioallantoic membrane model.

Formulations of hypericin (HY) with plasma protein have been conventionally used, but to date, no alternative pharmaceutical formulation has been developed for clinical use. Previously, it was reported that formulation of HY containing a biocompatible solvent and penetration enhancer, N-methyl pyrrolidone (NMP) was found to be effective for the delivery of HY across in vivo chick chorioallantoic membrane (CAM). This present study reports further investigations on the HY-NMP formulations in CAM implanted with human bladder cancer cells as a potential fluorescence diagnostic agent of cancer. The conventional formulation of HY (HY-HSA 0.5%) was included as control. The red-to-blue (I(R)/I(B)) intensity ratio of fluorescence images was used as a diagnostic algorithm, to differentiate the uptake of HY between tumor and adjacent regions on CAM. Results indicated that HY-NMP 0.05% was significantly better than HY-HSA 0.5%. The findings of the I(R)/I(B) ratios between tumor and adjacent tissues, indicated the potential of using NMP as an alternative to plasma protein in clinical fluorescence diagnosis with HY. The NMP formulations investigated were able to produce significantly higher contrast for tumor tissues and at earlier time points than was possible with HY-HSA 0.5%.

Animals↗
PubMed1983

Reversed-phase high-performance liquid chromatography used to monitor enzymatic cleavage of pyrrolidone carboxylic acid from regulatory peptides.

Sequence determination of peptides blocked by amino-terminal pyrrolidone carboxylic acid (PCA) has in the past been hampered by the lack of a reliable and efficient method for removing this residue. We report here a rapid, efficient enzymatic method for removal of PCA. Reversed-phase high-performance liquid chromatography is used to monitor the reaction and to separate unblocked peptide from the reaction product. The method allows direct sequence analysis of newly purified PCA blocked peptides, eliminating the need for complicated enzymatic digestions and chromatography to determine the amino-terminal residue. Only a few micrograms of peptide are required instead of the several milligrams needed in the past.

Amino Acids↗
PubMed2003

Study of interaction of poly(1-vinyl-2-pyrrolidone) with a surface of highly dispersed amorphous silica.

Interaction of poly(1-vinyl-2-pyrrolidone) with the surface of highly dispersed silica and character of its thermal destruction were investigated by means of ad-desorption measurement, vibration and electron spectroscopy, and thermal gravimetric analysis with programmed heating. The correlation between the character of polymer keeping on the surface of silicon dioxide and its thermal decomposition was established.

Journal Article↗
PubMed2002

Release of gentamicin sulphate from a modified commercial bone cement. Effect of (2-hydroxyethyl methacrylate) comonomer and poly(N-vinyl-2-pyrrolidone) additive on release mechanism and kinetics.

The influence of the (2-hydroxyethyl methacrylate) (HEMA) monomer addition as a comonomer to the cement liquid component and of a polymer, poly(N-vinyl-2-pyrrolidone) (PVP) to the solid component of a standard CMW-1 bone cement on gentamicin sulphate (GS) on its drug release properties have been studied. The addition of HEMA modifies the habit of the delivery curves. The incorporation of PVP into the cement matrix, apparently, did not very much modify the shape of the HEMA modified cement release curves, but led to a remarkable increase of the maximum amount of GS released. This effect was proportional to the PVP concentration incorporated. From the matrix composition and SEM data, a model based on the morphology of the matrix has been proposed. The cumulative amount of GS released by each slab Mt is most adequately fitted and represented by the equation Mt = c + at 1/2 + b[1 - exp(-nt)], which corroborates that the release occurs according to the model proposed. by means of three discrete mechanisms, namely: (i) a short-term initial elution due to the imperfections in the poly(methyl methacrylate) covering of the most external GS beads, burst effect by the buffer solution; (ii) followed by a fracture by stress cracking in an active media of the coated GS beads located on the external surface of the matrix where water molecules enter to dissolve GS molecules releasing them into the buffer solution by a diffusion-controlled process; and (iii) a third process in which the buffer solution penetrates into the internal voids and cracks creating a series of channels in a labyrinthic structure, which may facilitate the access of water molecules to the plastic-coated GS beads within the bulk matrix. This third process is enhanced by the incorporation of PVP beads as dissolved molecules within the matrix. This water-soluble additive is leachable, generating a highly porous structure in the cement. This HEMA and PVP modified cement may be used as a drug delivery system to modulate the GS release rate.

Anti-Bacterial Agents↗
PubMed2000

pH-sensitive freeze-dried chitosan-polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery.

The aim of this study was to develop a pH-sensitive chitosan/polyvinyl pyrrolidone (PVP) based controlled drug release system for antibiotic delivery. The hydrogels were synthesised by crosslinking chitosan and PVP blend with glutaraldehyde to form a semi-interpenetrating polymer network (semi-IPN). The semi-IPN formation was confirmed by Fourier transform infrared spectroscopic (FTIR) analysis. Semi-IPNs, viz, air-dried and freeze-dried, were compared for their surface morphology, wettability, swelling properties and pH-dependent swelling. Air- and freeze-dried membranes were also incorporated with amoxicillin and antibiotic release was studied. Porous freeze-dried hydrogels (pore diameter, 39.20+/-2.66 microm) exhibited superior pH-dependent swelling properties over non-porous air-dried hydrogels. A high octane contact angle (144.20+/-0.580) of hydrogel was indicative of its hydrophilic nature. Increased swelling of hydrogels, under acidic conditions, was due to the protonation of a primary amino group on chitosan, as confirmed by FTIR analysis. Freeze-dried membranes released around 73% of the amoxicillin (33% by air-dried) in 3 h at pH 1.0 and, thus, had superior drug-release properties to air-dried hydrogels. Freeze-dried membranes could serve as potent candidates for antibiotic delivery in an acidic environment.

Anti-Infective Agents↗
PubMed2002

Mucoadhesive drug carrier based on interpolymer complex of poly(vinyl pyrrolidone) and poly(acrylic acid) prepared by template polymerization.

To develop a new mucoadhesive drug carrier, poly(vinyl pyrrolidone) (PVP)/poly(acrylic acid) (PAA) interpolymer complexes were prepared by the template polymerization of acrylic acid using PVP as a template polymer. Fourier transform infrared results showed that the interpolymer complexes were formed by hydrogen bonds between the carboxyl groups of PAA and the carbonyl groups of PVP. The adhesive forces of the PVP/PAA interpolymer complexes were higher than that of commercial Carbopol 971. Moreover, the adhesive force and the release rate can be controlled by changing the mole ratios of PVP and PAA. The release rates of ketoprofen from the PVP/PAA interpolymer complexes showed pH-dependency, and were slower at lower pH. The release rate of ketoprofen from the complex seemed to be mainly controlled by the dissolution rate of the complex above a pK(a) of PAA (4.75) and by the diffusion rate below the pK(a). The prepared complex appears to be an adequate carrier for the mucoadhesive drug delivery system.

Acrylic Resins↗
PubMed2003

Galactosylated chitosan (GC)-graft-poly(vinyl pyrrolidone) (PVP) as hepatocyte-targeting DNA carrier. Preparation and physicochemical characterization of GC-graft-PVP/DNA complex (1).

Galactosylated chitosan was conjugated with poly(vinyl pyrrolidone) (PVP) as a hydrophilic group. The complex formation of GC-graft-PVP (GCPVP)/DNA complexes was confirmed by agarose gel electrophoresis. The morphology of the complex observed by atomic force microscopy had a compact and spherical shape, around 40 nm particle sizes at a charge ratio of 3. The binding strength of GCPVP 10K/DNA complex measured by ethidium bromide binding assay was superior to that of the GCPVP 50K/DNA one, probably attributable to its higher flexibility due to the smaller size, whereas the DNase I protection of GCPVP 10K/DNA complex was inferior to that of the GCPVP 50K/DNA one. This indicated that effective complex formation required both higher binding strength and minimal molecular weight of polycation enough to induce the condensation of DNA. The DNA-binding property of GCPVP mainly depended on the molecular weight of chitosan and composition of PVP.

Animals↗
PubMed2002

Developmental toxicity of N-methyl-2-pyrrolidone administered orally to rats.

The developmental toxicity of N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats after oral administration. Pregnant rats were given NMP at doses of 0 (distilled water), 125, 250, 500, and 750 mg/kg/day, by gavage, on gestational days (GD) 6 through 20. Significant decreases in maternal body weight gain and food consumption during treatment, and a reduction in absolute weight gain were observed at 500 and 750 mg/kg. The incidence of resorptions per litter was significantly higher than control at 500 mg/kg, and rose to 91% at 750 mg/kg. Examination of the foetuses revealed treatment-related malformations, including imperforate anus and absence of tail, anasarca, and malformations of the great vessels and of the cervical arches. The incidence of malformed foetuses per litter, and of litters with malformed foetuses was significantly increased at 500 and 750 mg/kg. At 250 mg/kg, one foetus showed malformations similar to those recorded at higher dosages. There was a dose-related decrease in foetal body weights (male, female, and total) that reached statistical significance at 250 mg/kg. A significant increase in incomplete ossification of skull bones and of sternebrae was also present at 500 and 750 mg/kg. In summary, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 250 and 125 mg/kg/day, respectively. Thus, oral administration of NMP produced developmental toxicity below maternally toxic levels.

Abnormalities, Drug-Induced↗
PubMed2003

Developmental toxicity of N-methyl-2-pyrrolidone in rats following inhalation exposure.

The developmental toxicity of inhaled N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats. Pregnant rats were exposed whole body to NMP vapours at concentrations of 0, 30, 60 and 120 ppm, 6 h/day, on gestational days (GD) 6 through 20. Maternal body weight gain was significantly decreased at 60 and 120 ppm on GD 6-13 and maternal food consumption was reduced at 120 ppm on GD 13-21. No significant difference in the gestational weight change corrected for the weight of the gravid uterus was observed, whatever NMP concentration. There were no adverse effects on embryo/fetal viability or evidence of teratogenicity at any concentration tested. Fetal toxicity indicated by reduced fetal weight was observed at 120 ppm. Thus, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 30 and 60 ppm, respectively.

Abnormalities, Drug-Induced↗
PubMed2000

Preparation and in-vitro evaluation of poly[N-vinyl-2-pyrrolidone-polyethylene glycol diacrylate]-chitosan interpolymeric pH-responsive hydrogels for oral drug delivery.

Biocompatible and biodegradable pH-responsive hydrogels based on N-vinyl pyrrolidone (NVP), polyethylene glycol diacrylate (PAC) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a free radical polymerization technique using azobisisobutyronitrile (AIBN) as initiator and N,N'-methylenebisacrylamide (BIS) as crosslinker. These hydrogels were subjected to equilibrium swelling studies in enzyme-free simulated gastric and intestinal fluids (SGF and SIF). These swelling studies clearly indicated that these hydrogels were swollen more in SGF when compared to SIF. Theophylline and 5-fluorouracil (5-FU) were entrapped into these hydrogels and equilibrium-swelling studies were carried out for the drug-entrapped gels in enzyme-free SGF and SIF. The in-vitro release profiles of the drugs were established in enzyme-free SGF. More than 50% of the entrapped drugs were released in the first 2 h at gastric pH and the rest of the drug release was slower.

Administration, Oral↗
PubMed2001

Acetylcholinesterase inhibitor SDZ ENA 713 (Rivastigmine) increases brain pyrrolidone carboxyl peptidase activity.

Pyroglutamyl-ended forms of amyloid-beta-peptide are present in senile plaques in some individuals with Alzheimer type dementia. Single oral administration of the acetylcholinesterase inhibitor SDZ ENA 713 (rivastigmine (+)-(S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylphenylcarbamate hydrogen tartrate) increases basal and K(+)-stimulated pyrrolidone carboxyl peptidase (Pcp) activity in mice frontal cortex synaptosomes in a dose-dependent manner. These results suggest that this drug may ameliorate ATD cognitive deficits acting not only facilitating cholinergic transmission but also avoiding the formation of pyroglutamyl-ended amyloid-beta-peptides (A beta pE) deposition through the activation of Pcp.

Animals↗
PubMed1997

Evidence for increased hydroxylation of pyrrolidone amino acid residues in the cuticle of mature Onchocerca volvulus.

To determine whether morphologic changes are accompanied by variations in the biochemical and antigenic properties of the cuticle of Onchocerca volvulus during development, we isolated and compared the 2-mercaptoethanol soluble cuticular proteins and the insoluble cuticlin from the predominant life-cycle stages occurring in man. SDS-PAGE analysis, before and after digestion with collagenase from Achromobacter iophagus, revealed that the polypeptide composition of the 2-mercaptoethanol-solubilised extracts from adult males and nodular microfilariae are quite distinct and that these extracts contained predominantly collagen-like proteins. Demonstrated by immunoblotting with a hyper immune patient serum pool (n = 107), five strongly reactive antigens with apparent molecular weights of 126, 68, 43, 37 and 33 kDa were detected in the extracts from adult males, while at least eight prominent and several weakly reactive components were detected in the extracts from nodular microfilariae. The overall amino acid composition of the cuticular extracts from the various stages demonstrates that: (a) the cuticle of the adult male stage is rich in glycine, pyrrolidone amino acids, and acidic amino acids or their amides, (b) eggshells are particularly poor in proline but rich in serine residues (14.5%), (c) nodular microfilariae cuticular extracts are poor in proline but rich in valine (9.0%) and lysine (7.3%) and (d) hydroxyproline and hydroxylysine are present in the cuticle of adults but absent in the juvenile life-cycle stages (nodular microfilariae and eggs). This study firstly, indicates that the composition of the cuticle of O. volvulus may thus, be quite distinct from one parasite stage to another and secondly, that the maturation of the parasite in the human host may be accompanied by the extensive hydroxylation of prolyl residues and to a lesser extent of lysyl residues in the predominantly collagen-like cuticular proteins.

Amino Acids↗
PubMed1999

X-ray structure of pyrrolidone carboxyl peptidase from the hyperthermophilic archaeon Thermococcus litoralis.

BACKGROUND: Pyrrolidone carboxyl peptidases (pcps) are a group of exopeptidases responsible for the hydrolysis of N-terminal pyroglutamate residues from peptides and proteins. The bacterial and archaeal pcps are members of a conserved family of cysteine proteases. The pcp from the hyperthermophilic archaeon Thermococcus litoralis is more thermostable than the bacterial enzymes with which it has up to 40% sequence identity. The pcp activity in archaea and eubacteria is proposed to be involved in detoxification processes and in nutrient metabolism; eukaryotic counterparts of the enzyme are involved in the processing of biologically active peptides. RESULTS: The crystal structure of pcp has been determined by multiple isomorphous replacement techniques at 1.73 A resolution and refined to an R factor of 18.7% (Rfree = 21.4%). The enzyme is a homotetramer of single open alpha/beta domain subunits, with a prominent hydrophobic core formed from loops coming together from each monomer. The active-site residues have been identified as a Cys143-His167-Glu80 catalytic triad. Structural homology to enzymes of different specificity and mechanism has been identified. CONCLUSIONS: The Thermococcus pcp has no sequence or structural homology with other members of the cysteine protease family. It does, however, show considerable similarities to other hydrolytic enzymes of widely varying substrate specificity and mechanism, suggesting that they are the products of divergent evolution from a common ancestor. The enhanced thermostability of the T. litoralis pcp may arise from hydrophobic interactions between the subunits and the presence of intersubunit disulphide bridges.

Animals↗
PubMed1992

Pyridoxol L,2-pyrrolidon-5 carboxylate prevents active fibroplasia in CCl4-treated rats.

In the present study we evaluated the protective activity of pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine) against CCl4 intoxication in rats, especially in relation to liver fibrosis. After 6 consecutive weeks of CCl4 treatment, the animals developed liver fibrosis and inflammation as revealed by histological analysis which also included semiquantitative scoring of these features. In addition the serum levels of the immunoreactive prolyl hydroxylase (SIRPH), an enzyme involved in the hydroxylation of the procollagen molecule, were significantly higher (44.2 +/- 16.3 micrograms/ml; P less than 0.005) in this group of animals than in controls (26.1 +/- 8.06). On the contrary, animals treated with CCl4 + metadoxine (200 mg/kg i.p.) had less severe liver fibrosis and normal SIRPH levels (21.5 +/- 14.6). These data suggest that metadoxine may be an effective pharmacological tool for preventing the progression of liver disease in rats exposed to CCl4 to cirrhosis.

Animals↗
PubMed1981

The effect of Trichinella spiralis on the rate of clearance of 51Cr-labelled sheep red blood cells and 125I-polyvinyl pyrrolidone from the bloodstream of mice.

Mice infected for one to eight weeks with Trichinella spiralis cleared either 51Cr-labelled sheep red blood cells (SRBC) or 125I-polyvinyl pyrrolidone (PVP) given intravenously. PVP was cleared more rapidly from the blood of mice infected for one week than from uninfected mice with older infections which behaved in a similar manner to the controls. SRBC were consistently cleared faster from the blood of mice infected for one week than from normal mice. If the infections were older than this a more rapid clearance was also demonstrated as long as the infections were reasonably heavy.

Animals↗
PubMed2004

Unusually slow denaturation and refolding processes of pyrrolidone carboxyl peptidase from a hyperthermophile are highly cooperative: real-time NMR studies.

The refolding rate of heat-denatured cysteine-free pyrrolidone carboxyl peptidase (PCP-0SH) from Pyrococcus furiosus has been reported to be unusually slow under some conditions. To elucidate the structural basis of the unusually slow kinetics of the protein, the denaturation and refolding processes of the PCP-0SH were investigated using a real-time 2D (1)H-(15)N HSQC and CD experiments. At 2 M urea denaturation of the PCP-0SH in the acidic region, all of the native peaks in the 2D HSQC spectrum completely disappeared. The conformation of the PCP-0SH just after removal of 6 M GuHCl could be observed as a stable intermediate (D(1) state) in 2D HSQC and CD experiments, which is similar to a molten globule structure. The D(1) state of the PCP-0SH, which is the initial state of refolding, corresponded to the state at 2 M urea and seemed to be the denatured state in equilibrium with the native state under the physiological conditions. The refolding of PCP-0SH from the D(1) state to the native state could be observed to be highly cooperative without any intermediates between them, even if the refolding rate was quite slow. In the higher concentration of denaturants, PCP-0SH showed HSQC and CD spectra characteristic of completely unfolded proteins called the D(2) state. The unusually slow refolding rate was discussed as originating in the conformations in the transition state and/or the retardation of reorganization in an ensemble of nonrandom denatured structures in the D(1) state.

Archaeal Proteins↗
PubMed2006

Completely buried, non-ion-paired glutamic acid contributes favorably to the conformational stability of pyrrolidone carboxyl peptidases from hyperthermophiles.

Pyrrolidone carboxyl peptidases (PCPs) from hyperthermophiles have a structurally conserved and completely buried Glu192 in the hydrophobic core; in contrast, the corresponding residue in the mesophile protein is a hydrophobic residue, Ile. Does the buried ionizable residue contribute to stabilization or destabilization of hyperthermophile PCPs? To elucidate the role of the buried glutamic acid in stabilizing PCP from hyperthermophiles, we constructed five Glu192 mutants of PCP-0SH (C142S/C188S, Cys-free double mutant of PCP) from Pyrococcus furiosus and examined their thermal and pH-induced unfolding and crystal structures and compared them with those of PCP-0SH. The stabilities of apolar (E192A/I/V) and polar (E192D/Q) mutants were less than PCP-0SH at acidic pH values. In the alkaline region, the mutant proteins, except for E192D, were more stable than PCP-0SH. The thermal stability data and theoretical calculations indicated an apparent pKa value > or = 7.3 for Glu192. Present results confirmed that the protonated Glu192 in PCP-0SH forms strong hydrogen bonds with the carbonyl oxygen and peptide nitrogen of Pro168. New intermolecular hydrogen bonds in the E --> A/D mutants were formed by a water molecule introduced into the cavity created around position 192, whereas the hydrogen bonds disappeared in the E --> I/V mutants. Structure-based empirical stability of mutant proteins was in good agreement with the experimental results. The results indicated that (1) completely buried Glu192 contributes to the stabilization of PCP-0SH because of the formation of strong intramolecular hydrogen bonds and (2) the hydrogen bonds by the nonionized and buried Glu can contribute more than the burial of hydrophobic groups to the conformational stability of proteins.

Calorimetry, Differential Scanning↗