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PubMed2001

Fourier transform Raman spectroscopic study of the interaction of water vapor with amorphous polymers.

Water associated with amorphous polymers is known to affect their chemical and physical properties. The purpose of this study was to investigate the nature of water-polymer interactions for some polymers of pharmaceutical interest. Using Raman spectroscopy, polymer-water hydrogen bond interactions were probed for two molecular weight grades of poly(vinylpyrrolidone), namely PVP K90 and PVP K12, and also for poly(vinylacetate) and poly(vinyl pyrrolidone-co-vinyl acetate). Water vapor absorption isotherms were obtained for the polymers, and the effect of the absorbed water on the glass transition temperature was determined. A knowledge of the water content and physical state of the polymer was used to aid interpretation of Raman spectral changes. The strength of the hydrogen bond formed with water was found to depend on the chemistry of the polymer, with the pyrrolidone group interacting more strongly than the acetate group. However, minor differences were also observed between the degree of interaction of water and polymer for PVP K12 and PVP K90 at some water contents. This result is attributed to differences in the structural relaxation changes accompanying plasticization by water for the two molecular weight grades. Using principal components analysis of the spectral data, it was also possible to differentiate between samples in the rubbery state and samples in the glassy state. In conclusion, water sorbed into polymers causes changes in the polymer Raman spectra not only because of hydrogen bonding, but also as a result of the plasticizing effect of water on polymer mobility.

Hydrogen Bonding↗
PubMed2001

Influences of alkyl group chain length and polar head group on chemical skin permeation enhancement.

Previous investigations in our laboratory on the influence of the n-alkanols and the 1-alkyl-2-pyrrolidones as skin permeation enhancers for steroid molecules as permeants demonstrated that the enhancer potencies (based on aqueous concentration values) of these two homologous series were the same when compared at the same alkyl chain length; that is, the contribution of the hydroxyl group and that of the pyrrolidone group to enhancer potency were the same. The purpose of the present study was to further investigate what was believed to be a somewhat surprising finding, and two additional homologous series, the 1,2-alkanediols and N,N-dimethylalkanamides, were selected for study as enhancers. Corticosterone (CS) flux enhancement along the lipoidal pathway of hairless mouse skin stratum corneum was determined with 1,2-hexane-, 1,2-octane-, and 1,2-decanediol and with N,N-dimethylhexanamide, N,N- dimethylheptanamide, N,N-dimethyloctanamide, and N,N-dimethylnonanamide as enhancers. The enhancement factor (E) for the lipoidal pathway was calculated from the CS permeability coefficient and the CS solubility data over a 4 to 100 range of E values. Comparisons of the enhancer potencies of all four homologous series revealed that the enhancer potencies of all were very nearly the same when compared at equal alkyl group chain length. Moreover, the contribution of each of the polar head groups toward the enhancer potency was essentially constant, independent of the alkyl group chain length. It was reasoned that this outcome was either the result of the random selection of four polar head groups making the same contribution to enhancer potency or the result of these particular polar head groups not contributing to enhancer potency. To test the hypothesis that the former was more likely than the latter and that a suitable semipolar organic phase may mimic the microenvironment of the polar head group at the site of enhancer action, n-octanol-phosphate buffered saline (PBS) and n-hexane-PBS partition coefficients were determined for all the enhancers. The n-octanol-PBS partition coefficients for the enhancers, but not the n-hexane-PBS partition coefficients, were very nearly the same when compared at equal alkyl group chain lengths; this result supports the hypothesis that each of the four polar head groups likely contributes the same toward the enhancer potency and locates in the semipolar region of the hairless mouse skin stratum corneum lipid bilayers, which is well-approximated by water-saturated n-octanol.

Alkanes↗
PubMed2006

Bioadhesive monolayer film for the in vitro transdermal delivery of sumatriptan.

The work presented here aims to develop a bioadhesive monolayer film containing sumatriptan as adjuvant for the treatment of headache pain in a severe migraine attack. Permeation experiments were performed from the films prepared and from the respective solution, to evaluate the relevant permeation parameters. The effect of the penetration enhancers Transcutol, 2-pyrrolidone, and polyethylene glycol 600 was evaluated. The results obtained show that Transcutol and 2-pyrrolidone decreased sumatriptan permeation from solution, whereas a modest increase was produced by polyethylene glycol 600. The enhancers produced the same effects when they were included in the film. Compared to solution, the film showed a higher sumatriptan flux in the early times of the experiment. When the film was applied in occlusive conditions the profiles were much higher, indicating the importance of patch drying. Concerning skin retention, the bioadhesive film produced a reduction of the amount of sumatriptan remaining in the skin, but this can be advantageous in the control of drug input, since it reduces the reservoir effect in the skin and allows for an immediate interruption of drug input when the patch is removed.

Administration, Cutaneous↗
PubMed1986

Pharmacodynamic measurement of percutaneous penetration enhancement in vivo.

Enhanced skin penetration of hexyl nicotinate was measured in human subjects using laser Doppler velocimetry (LDV). The local pharmacodynamic response (vasodilatation) to hexyl nicotinate permitted the kinetics and extent of penetration to be evaluated following topical application of 10 mM drug in a 60:40 v/v propylene glycol: isopropyl alcohol vehicle. Prior to hexyl nicotinate administration, the application site was either untreated (control) or subjected to one of four 30-min pretreatments: (a) occlusion with a polypropylene chamber; (b) occlusion (as in a) in the presence of 0.3 mL of the vehicle; (c) occlusion (as in a) in the presence of 0.3 mL of the vehicle containing 25% 2-pyrrolidone; and (d) occlusion (as in a) in the presence of 0.3 mL of the vehicle containing 25% laurocapram (1-dodecylhexahydro-2H-azepin-2-one). The time-course and magnitude of the LDV response were characterized by the onset of action, time to peak, peak height, and area under the curve (AUC). The onset of action and time to peak were significantly shortened, and the peak height and AUC significantly increased with pretreatments a-d. For example, time to peak values were 35 +/- 4, 29 +/- 3, 22 +/- 5, 19 +/- 4, and 17 +/- 4 min for control and pretreatments a-d, respectively (n = 8). Pretreatments with vehicle, vehicle plus 2-pyrrolidone, and vehicle plus laurocapram did not cause LDV-detectable alterations in skin blood flow. The data support, therefore, a novel, simple, noninvasive, and objective demonstration of enhanced skin penetration of hexyl nicotinate in humans.

Adult↗
PubMed1994

A simple HPLC technique for accurate monitoring of mammalian cell metabolism.

We have developed a simple and accurate isocratic HPLC method, without any prederivatisation, for the determination of glucose, lactate, glutamine, glutamate, pyrrolidone carboxylic acid and alanine in samples from mammalian cell cultures. The method has been successfully validated with enzyme analysis for each of the compounds. Quantification of pyrrolidone carboxylic acid makes the correction for glutamine decrease due to chemical decomposition very simple and accurate, and avoids some possibly erroneous calculations.

Amino Acids↗
PubMed2006

Stabilization of two-phase octanol/water flows inside poly(dimethylsiloxane) microchannels using polymer coatings.

In this paper we present our first results on the realization of stable water/octanol, two-phase flows inside poly(dimethylsiloxane) (PDMS) microchannels. Native PDMS microchannels were coated with high molecular weight polymers to change the surface properties of the microchannels and thus stabilize the laminar flow profile. The polymers poly(2-hydroxyethyl methacrylate), poly(vinyl pyrrolidone), poly(ethylene oxide), poly(ethylene glycol), and poly(vinyl alcohol) were assessed for their quality as stabilization coatings after deposition from flowing and stationary solutions. Additionally, the influence of coating the microchannels homogeneously with a single kind of polymer or heterogeneously with two different polymers was investigated. From the experimental observations, it can be concluded that homogeneous polymer coatings with poly(2-hydroxyethyl methacrylate) and poly(vinyl pyrrolidone) led to the effective stabilization of laminar water/octanol flows. Furthermore, heterogeneous coatings led to two-phase flows which had a better-defined and more stable interface over long distances (i.e., 40-mm-long microchannels). Finally, the partitioning of fuchsin dye in the coated microchannels was demonstrated, establishing the feasibility of the use of the polymer-coated PDMS microchannels for determination of logP values in laminar octanol/water flows.

Dimethylpolysiloxanes↗
PubMed1988

A radiochemical assay for a NADP+-specific gamma-glutamate semialdehyde dehydrogenase extracted from mitochondrial membrane of rat intestinal epithelial cells.

A radiochemical assay has been developed for a NADP+-specific gamma-glutamate semialdehyde dehydrogenase from rat intestinal epithelial cells. The spectrophotometric assay utilized to measure the enzyme in bacterial cell homogenates is not sensitive enough for homogenates from rat mitochondria, which require an assay that can measure as little as 0.5 nmol NADPH formed/min/ml extract. The assay described here is sensitive to 0.1 nmol product formed/min/ml of extract and employs the use of [3H]pyrroline 5-carboxylate which is phosphorylated and oxidized by the enzyme to gamma-[3H]glutamyl phosphate, a product that decomposes to [3H]pyrrolidone 5-carboxylate. The latter product is separated from the substrate by ion-exchange chromatography. In order to correct for any product loss during separation by ion-exchange [14C]pyrrolidone 5-carboxylate is added as an internal standard to the deproteinized assay mixture. Under the assay conditions described mammalian gamma-glutamate semialdehyde dehydrogenase activity is linear with respect to time and protein concentration. Comparison between the kinetic parameters reported for the bacterial enzyme and those reported here for the mammalian enzyme indicate similarities in the pH optima as well as a requirement for phosphate. Kinetic studies on mammalian enzyme yield apparent Km values of 1.8 mM for pyrroline 5-carboxylate, 0.2 mM for NADP+, and 11.3 mM for phosphate.

Aldehyde Oxidoreductases↗
PubMed1987

Structural requirements for affinity and efficacy of N-(4-amino-2-butynyl)succinimides at muscarinic receptors in the guinea-pig ileum and urinary bladder.

The muscarinic activities on the isolated guinea-pig ileum and urinary bladder of some N-(4-amino-2-butynyl)succinimides, modified only in the amino group, were resolved into receptor affinity and efficacy components. The structural requirements for high affinity and high efficacy were quite different. Cyclic tertiary amino moieties generally favoured high affinity, while small acyclic amino and ammonium groups favoured high efficacy. On the ileum, dissociation constants and relative efficacies of the succinimides were highly correlated (r = 0.94-0.97) with those of the identically modified N-(4-amino-2-butynyl)-2-pyrrolidones. This observation suggests that N-(4-amino-2-butynyl)succinimides and 2-pyrrolidones bind to and activate muscarinic receptors in a similar fashion. In spite of their agonist properties on the ileum, the succinimides studied were agonists, partial agonists or competitive antagonists on the urinary bladder. However, dissociation constants and relative efficacies of the compounds showed good agreement in the two tissues. It therefore appears that muscarinic receptors in the guinea-pig ileum and urinary bladder are pharmacologically similar. The large differences observed in agonist potency and relative maximal responses between the two tissues were explained by a greater receptor reserve for muscarinic agonists in the ileum than in the bladder.

Animals↗
PubMed1985

Primary structure and subunit stoichiometry of F1-ATPase from bovine mitochondria.

The enzyme complex F1-ATPase has been isolated from bovine heart mitochondria by gel filtration of the enzyme released by chloroform from sub-mitochondrial particles. The five individual subunits alpha, beta, gamma, delta and epsilon that comprise the complex have been purified from it, and their amino acid sequences determined almost entirely by direct protein sequence analysis. A single overlap in the gamma-subunit was obtained by DNA sequence analysis of a complementary DNA clone isolated from a bovine cDNA library using a mixture of 32 oligonucleotides as the hybridization probe. The alpha, beta, gamma, delta and epsilon subunits contain 509, 480, 272, 146 and 50 amino acids, respectively. Two half cystine residues are present in the alpha-subunit and one in each of the gamma- and epsilon-chains; they are absent from the beta- and delta-subunits. The stoichiometry of subunits in the complex is estimated to be alpha 3 beta 3 gamma 1 delta 1 epsilon 1 and the molecular weight of the complex is 371,135. Mild trypsinolysis of the F1-ATPase complex, which has little effect on the hydrolytic activity of the enzyme, releases peptides from the N-terminal regions of the alpha- and beta-chains only; the C-terminal regions are unaffected. Sequence analysis of the released peptides demonstrates that the N terminals of the alpha- and beta-chains are ragged. In 65% of alpha-chains, the terminus is pyrrolidone carboxylic acid; in the remainder this residue is absent and the chains commence at residue 2, i.e. lysine. In the beta-subunit a minority of chains (16%) have N-terminal glutamine, or its deamidation product, glutamic acid (6%), or the cyclized derivative, pyrrolidone carboxylic acid (5%). A further 28% commence at residue 2, alanine, and 45% at residue 3, serine. The delta-chains also are heterogeneous; in 50% of chains the N-terminal alanine residue is absent. The sequences of the alpha- and beta-chains show that they are weakly homologous, as they are in bacterial F1-ATPases. The sequence of the bovine delta-subunit of F1-ATPase shows that it is the counterpart of the bacterial epsilon-subunit. The bovine epsilon-subunit is not related to any known bacterial or chloroplast H+-ATPase subunit, nor to any other known sequence. The counterpart of the bacterial delta-subunit is bovine oligomycin sensitivity conferral protein, which helps to bind F1 to the inner mitochondrial membrane.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1992

Matrix entrapment of glucose oxidase by gamma irradiation.

In this study, matrix entrapment of the enzyme glucose oxidase was achieved through gamma irradiation of monomers N-vinyl pyrrolidone, 2-hydroxyethyl methacrylate and their mixture. To test the effect of radiation on entrapment efficiency, retention of activities and properties of the system, duration and temperature were varied. The reusability of the resultant products was tested. It was generally found that inclusion of the hydrophilic monomer N-vinyl pyrrolidone into the matrix increased the water content, entrapment efficiency and enzyme activity. gamma irradiation did not have a detrimental effect on the activity of pure enzyme when exposure was at -196 degrees C, but this radioresistance was less at higher temperatures. Infrared spectroscopy indicated that there was no chemical binding between the matrix and the enzyme. Repeated use studies revealed a gradual loss of activity in all of the samples tested for 10 runs.

Biocompatible Materials↗
PubMed1992

Studies on the effect of degree of hydrophilicity on tissue response of polyurethane interpenetrating polymer networks.

Interpenetrating polymer networks of polyurethane and vinyl monomers such as polyacrylamide, polyvinyl pyrrolidone, poly(hydroxyethyl methacrylate) and poly(methyl methacrylate) were implanted intramuscularly in rabbits. Attempts were made to correlate the morphological aspects of the interpenetrating polymer networks to their histological response. A relatively increased hydrophilicity of hydrophobicity of the interpenetrating polymer networks as in the case of polyurethane-polyvinyl pyrrolidone and polyurethane-poly(methyl methacrylate) interpenetrating polymer networks, respectively, could elicit an inert response whilst degradation of materials promoted reactivity.

Acrylic Resins↗
PubMedDate not supplied

Isolation and characterization of rabbit gastrin.

The heptadecapeptide form the rabbit gastrin was extracted from 16 rabbit antra and purified by a combination of DEAE Sephadex, C-18 SEP PAK cartridges, fast performance liquid chromatography (FPLC) and reverse phase high pressure liquid chromatography (HPLC) steps. After the HPLC purification, a sharp, single peak of gastrin-like immunoreactivity was detected that had the same absorption to immunoreactivity ratio as human gastrin. An amino terminal pyrrolidone carboxylic acid blocking group was removed by incubation with pyrrolidone carboxylic peptidase. The amino acid analysis, microsequence analysis and mass spectrometry all confirmed the structure of rabbit gastrin being pQGPWLQEEEEAYGWMDFamide. This sequence is identical to human gastrin-17 except for glutamine in position 6 which replaces glutamate in human gastrin. Both sulfated and unsulfated rabbit gastrin-17 were characterized by mass spectrometry.

Amino Acid Sequence↗
PubMed1976

The influence of glutamine, its decomposition products, and glutaminase on the transformation of human and mouse lymphocytes.

The extent of blast transformation for human and BALB/c mouse lymphocytes has been examined over a wide range of glutamine concentrations with several agents which initiate blastogenesis. Maximum [3H] thymidine incorporation was seen at 0.5 mM glutamine for lymphoid tissues stimulated in the following manner: human and BALB/c splenic and peripheral blood lymphocytes with phytohemagglutinin, BALB/c splenic lymphocytes with lipopolysaccharide, and BALB/c vs C3H/HeJ two-way mixed lymphocyte cultures. The inhibition of blastogenesis exerted by glutamine concentrations greater than 0.5 mM could not be reversed by washing and reculturing the cells at 0.5 mM glutamine. To elucidate the reason for inhibition by higher glutamine concentrations, the products of spontaneous glutamine decomposition, L-2-pyrrolidone-5-carboxylic acid and ammonia were tested for their in vitro influence on BALB/c splenocyte blastogenesis. Pyrrolidone-carboxylic acid, in concentrations up to 5 mM, was without effect. In contrast, ammonia concentrations exceeding 1 mM became increasingly more inhibitory. The genesis of inhibitory levels of ammonia in culture medium was confirmed and has been considered as primarily responsible for inhibiton by high glutamine. Addition of Escherichia coli glutaminase (pH optimum 4.9) to cultures of BALB/c splenocytes or human peripheral blood lymphocytes had no effect on either the extent of blastogenesis of these tissues or the glutamine levels in their culture medium.

Adult↗
PubMed1989

High-performance liquid chromatographic determination of metabolic products for fermentation control of mammalian cell culture: analysis of carbohydrates, organic acids and orthophosphate using refractive index and ultraviolet detectors.

A method for the determination of carbohydrate substrates and excreted metabolic end-products of cell culture supernatants using a strong cation-exchange column in the H+ form has been developed. Organic acids and carbohydrates can be determined in addition to orthophosphoric acid. Pyrrolidone carboxylic acid, resulting from chemical conversion of the amino acid glutamine during the incubation of fresh medium and during the fermentation process, can be determined. The chromatographic method allows the correction of glutamine uptake values for physiological studies. Measured values of pyrrolidone carboxylic acid in supernatants of human hybridoma cell line show that it cannot be consumed by the cells. This technique allows the separation of major metabolites used in process optimization. Peak homogeneity is proved by on-line monitoring of the effluent with an ultraviolet (214 nm) and a refractive index detector connected in series.

Acids↗
PubMed2004

Penetration enhancers.

One long-standing approach for improving transdermal drug delivery uses penetration enhancers (also called sorption promoters or accelerants) which penetrate into skin to reversibly decrease the barrier resistance. Numerous compounds have been evaluated for penetration enhancing activity, including sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common excipient in topically applied dosage forms), surfactants (also common in dosage forms) and terpenes. Many potential sites and modes of action have been identified for skin penetration enhancers; the intercellular lipid matrix in which the accelerants may disrupt the packing motif, the intracellular keratin domains or through increasing drug partitioning into the tissue by acting as a solvent for the permeant within the membrane. Further potential mechanisms of action, for example with the enhancers acting on desmosomal connections between corneocytes or altering metabolic activity within the skin, or exerting an influence on the thermodynamic activity/solubility of the drug in its vehicle are also feasible, and are also considered in this review.

Adjuvants, Pharmaceutic↗
PubMed2004

Potent inhibitors of the HIV-1 protease incorporating cyclic urea P1-P2 scaffold.

We have developed synthetic approaches to novel analogues of 2-imidazolidinone scaffold 2, which was found to be an effective P1-P2 mimetic in HIV-1 protease inhibitor 4. This enabled a rapid synthesis of analogues of 4 and subsequently allowed us to evaluate and rationalize the SAR. Accordingly, trans relationship of P1 and P2 substituents in the P1-P2 mimetic, as found in a related 2-pyrrolidone-based scaffold 1, was found necessary for high potency against HIV-1 protease. Results of this study provided further rationale towards subsequent optimization of 2-pyrrolidone-based lead 3, which led us to potent and drug-like HIV-1 protease inhibitors described in a follow-on report (Bioorg. Med. Chem. Lett. 2004, 14, in press. ).

Cyclization↗
PubMed2005

Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats.

Nefiracetam is a novel pyrrolidone-type nootropic agent, and it has been reported to possess a potential for antiepileptic therapy as well as cognition-enhancing effects. We investigated the anticonvulsant and neuroprotective effects of nefiracetam in kainic acid-induced seizures of rats, compared with levetiracetam and standard antiepileptic drugs. Subcutaneous injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas). Nefiracetam (25, 50 and 100 mg/kg po) had no effect on the behavioral seizures and dose-dependently inhibited the hippocampal damage. In contrast, levetiracetam, a pyrrolidone-type antiepileptic drug, inhibited neither. Valproic acid and ethosuximide prevented the hippocampal damage without attenuating the behavioral seizures as nefiracetam. Zonisamide and phenytoin did not inhibit the behavioral seizures, while zonisamide enhanced the hippocampal damage and phenytoin increased the lethality rate. Carbamazepine inhibited the behavioral seizures at 50 mg/kg and enhanced that at 100 mg/kg, and it completely inhibited the hippocampal damage at both doses. We have previously reported that anticonvulsant spectrum of nefiracetam paralleled that of zonisamide, phenytoin or carbamazepine in standard screening models. However, the pharmacological profile of nefiracetam was closer to valproic acid or ethosuximide than that of zonisamide, phenytoin or carbamazepine in this study. These results suggest that anticonvulsant spectrum and mechanism of nefiracetam are distinct from those of standard antiepileptic drugs, and nefiracetam possesses a neuroprotective effect that is unrelated to seizure inhibition.

Animals↗
PubMed2005

Dissolution rate improvement of poorly water-soluble drugs obtained by adsorbing solutions of drugs in hydrophilic solvents onto high surface area carriers.

The dissolution rate of the model drugs carbamazepine and nifedipine was improved by adsorbing solutions of the drugs in hydrophilic non-volatile or volatile solvents onto carriers with a large surface area. This was accomplished by dissolving the drug in methanol or the non-toxic hydrophilic liquids PEG 400 or 2-pyrrolidone, and adsorbing these solutions onto the surface of silica (Aerosil) or crosslinked polyvinylpyrrolidone (Kollidon CL-M). The solvent binding capacities decreased in the order of methanol, PEG 400, 2-pyrrolidone for Aerosil 200, 300, 380 and for Kollidon CL-M. Kollidon bound less liquid than Aerosil because of the smaller surface area. Differential scanning calorimetry measurements showed higher interactions between drugs and Kollidon compared to Aerosil, suggesting a low aggregation of precipitated drug particles. The drug release from the adsorbent systems was enhanced when compared to micronized drug and independent of the drug loading in the investigated range. The drugs were also dissolved in various liquid, paste-like or solid solubilisers (polyoxyl-40-hydrogenated castor oil (Cremophor RH 40), macrogol-15-hydroxystearate (Solutol HS), poloxamers (Lutrol F68, Pluronic F87NF and Pluronic L44NF) and adsorbed onto Kollidon. These adsorbent systems also exhibited an increased dissolution rate when compared to pure drug.

Adsorption↗