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PubMed1999

The effects of pH and mixed solvent systems on the solubility of oxytetracycline.

The solubility of oxytetracycline (OTC) in aqueous and mixed solvent systems was studied. The effects of pH and cosolvent composition on the solubility and apparent dissociation constants (pKa') of OTC were determined by a solubility method. The pKa' values of OTC in each mixed solvent system were estimated and used to generate expressions for predicting drug solubility in each cosolvent as a function of pH. Cosolvent systems of PEG 400, propylene glycol, glycerin, and 2-pyrrolidone were studied in the pH range of 2.5-9. Solubility results showed increased solubility with increased cosolvent concentration, especially in 2-pyrrolidone solvent systems. These results also showed that cosolvents enhanced drug solubility through either their effects on polarity of the solvent medium or complex formation with OTC. Aqueous and mixed solvent systems at lower pH values resulted in higher OTC solubilization because the drug existed primarily in its cationic form. A mass balance equation including all ionic species of OTC allowed for estimation of the intrinsic solubilities and pKa' values in each solvent system. pKa' values and intrinsic solubility of the OTC zwitterion increased with increasing cosolvent content. These parameters allowed prediction of drug solubility within the pH range and cosolvent concentrations used in this study.

Anti-Bacterial Agents↗
PubMed2003

Description of Comamonas aquatica comb. nov. and Comamonas kerstersii sp. nov. for two subgroups of Comamonas terrigena and emended description of Comamonas terrigena.

Three clusters of isolates have previously been defined within the species Comamonas terrigena, on the basis of DNA-rRNA and DNA-DNA hybridization data, and of protein electrophoretic patterns and immunotyping. More detailed characterization in the current study shows that representatives of these three groups can also be differentiated phenotypically from each other. Strains of C. terrigena sensu stricto (C. terrigena DNA group 1) are pyrrolidone aminopeptidase-positive, do not grow at 40 degrees C, are L-alanine-positive and are always negative for 4-hydroxybenzoate. Strains of C. terrigena DNA groups 2 and 3 are pyrrolidone aminopeptidase-negative; the former is the only group that is tyrosine-negative, and only the latter can grow at 42 degrees C (with an optimal growth temperature of 40 degrees C). These findings are corroborated by differences in 16S rDNA sequence and tRNA intergenic spacer lengths. Therefore, it is proposed to rename C. terrigena DNA group 2 [containing former Aquaspirillum aquaticum and E. Falsen (EF) group 10 strains] as Comamonas aquatica sp. nov., and C. terrigena DNA group 3 (containing former EF group 10 strains) as Comamonas kerstersii sp. nov.

Bacterial Proteins↗
PubMed1977

Synthesis and biological activity of position 1 analogs of LH-RH.

(Formyl-sarcosine)1-LH-RH (I), (acetyl-sarcosine)1-LH-RH (II), (2-pyrrolidone-4-carboxylic acid)1-LH-RH (III), (N-methyl-2-pyrrolidone-4-carboxylic acid)1-LH-RH (IV, hydroxyproline1-LH-RH (V) and (cylcopentane-carboxylic acid)1-LH-RH (VI) were synthesized by solid phase methods on a benzhydrylamine resin support. Peptides I-IV were assayed for LH- and FSH-releasing activity over a 4-h period after subcutaneous infection into immature male rats in order to detect any prolongation ofactivity. The peptides were found to have the following integrated LH-releasing activities compared with LH-RH: I, 64%; II, 72%; III, 19%; IV, 58%. None of the peptides were found to be longer acting than LH-RH. Peptides V and VI were far less active, 0.001% and 1.4%, respectively.

Amino Acids↗
PubMed1982

Solid phase synthesis of the protected 43-55 tridecapeptide of the heavy chain of myeloma immunoglobin M603, employing cyclohexyl ester protection for glutamic acid.

A protected tridecapeptide of the sequence Boc-Lys(2CIZ)-Arg(Tos)-Leu-Glu (OcHex)-Trp(For)-Ile-Ala-Ala-Ser(Bzl)-Arg(Tos)-Asn-Lys(2CIZ)-Gly-OH, representing residues 43-55 of the variable region of the heavy chain of mouse myeloma protein M603, was synthesized. It was assembled by a stepwise solid phase method designed to give a fully protected peptide in high yield and purity with minimal side reactions. Thus, the peptide chain was attached as an alpha-methyl phenacyl ester to a 2-bromopropionyl-resin. After the synthesis the protected peptide fragment was obtained in 89% yield by photolytic cleavage from the resin. The peptide was purified by multiple precipitation and column chromatography. It was shown to be homogeneous by reverse phase high pressure liquid chromatography, and it had the correct amino acid composition and sequence. In the course of this work it was shown that tert.-butyloxycarbonyl-amino acids caused the formation of significant amounts of pyrrolidone carboxylic acid residues during the coupling reaction when a gamma-benzyl glutamyl residue was NH2-terminal. Other weak-acid additives also caused this chain terminating side reaction. The cyclization was markedly suppressed by protection of the glutamyl side chain as a cyclohexyl ester. With this protecting group, no evidence of pyrrolidone carboxylic acid formation could be detected in the tridecapeptide 43-55.

Amino Acid Sequence↗
PubMed1993

Effects of remoxipride's metabolites on dopamine D2 receptors and receptor functions in the rat.

The main metabolites of remoxipride formed in rat and man were examined for their affinities for the [3H] SCH 23390-labelled DA D1 and [3H]-raclopride-labelled D2 receptors in rat striatal homogenates. In addition, their effectiveness in blocking postsynaptic DA receptor activity in vivo was measured by the use of several different test models in the male rat. Phenolic metabolites formed mainly in the rat retained (similar to remoxipride) their selectivity for the D2 receptor with very low affinities for the D1 receptor. The pyrrolidone metabolites formed mainly in man showed very low affinities for both the D1 and D2 receptors. The ability of the metabolites to block postsynaptic DA receptor activity in vivo correlated with their affinities for the D2 receptor. Among the metabolites tested, the phenolic compounds FLA 797 (-) and FLA 908 (-) were much more effective than remoxipride in inducing catalepsy, which is consistent with a higher affinity for [3H] raclopride labelled striatal D2 receptors. However, analysis of the effectiveness of the DA receptor blockade (blockade of d-amphetamine locomotion or DA agonist hypothermia) after intraperitoneal or subcutaneous administration suggested that FLA 797 (-)/FLA 908 (-) may only contribute marginally to the D2 receptor-blocking activity of remoxipride in the rat. This conclusion was further supported by the observation that the atypical antipsychotic profile of remoxipride was not mimicked by the active metabolites. The weak DA D2 blocking effect of the pyrrolidone metabolites indicated that remoxipride is responsible for the clinical action.

Amphetamine↗
PubMed2004

Preformulation stability of Spantide II, a promising topical anti-inflammatory agent for the treatment of psoriasis and contact dermatitis.

Substance P is readily expressed in skin inflammatory disorders such as psoriasis and contact dermatitis. Spantide II is a peptide (MW 1668.76) that specifically binds to neurokinin-1 receptor (NKR-1) and blocks inflammation associated with substance P. The anti-inflammatory property of Spantide II makes it a suitable candidate to be studied as a topical formulation for the treatment of dermal inflammatory disorders. The objective of this study was to investigate the influence of pH, temperature, salt concentration and concentration on the aqueous stability of Spantide II. The stability of Spantide II was also assessed by circular dichroic (CD) spectroscopy and mass spectrometry (MS). The influence of various dermatological vehicles (ethanol, Transcutol, propylene glycol, N-methyl-2-pyrrolidone (NMP), ethyl oleate, isopropyl myristate and laurogylcol FCC (LFCC)) on the stability of Spantide II was investigated. A precise high-performance liquid chromatography (HPLC) assay was developed for analysis of Spantide II. At higher temperature (40 degrees C) the stability of Spantide II decreased with increase in pH (P < 0.05). Change in salt concentration did not appreciably affect the stability of Spantide II (P > 0.05). The concentration of Spantide II in the solution had no significant influence on its stability (P > 0.05). CD spectroscopy studies showed that Spantide II has a relatively stable alpha-helix structure in the liquid state. The stability of Spantide II was affected by the type of vehicle used in the study (P < 0.01) at different temperatures (P < 0.05). Spantide II at high temperature undergoes lysine-proline diketopiperazine degradation as evident in MS data. Spantide II was relatively more stable in ethyl oleate-ethanol, ethanol-water, ethanol and N-methyl-2-pyrrolidone. The results of this study indicate that ethyl oleate-ethanol (1:1) and ethanol-water (1:1) could be used as potential vehicles in the development of topical formulations of Spantide II.

Administration, Topical↗
PubMed2006

Preparation and characterization of (PVP + NaClO4) electrolytes for battery applications.

A sodium ion-conducting polymer electrolyte based on polyvinyl pyrrolidone (PVP) complexed with NaClO(4) was prepared using the solution-cast technique. The cathode film of V(2)O(5) xerogel modified with polyvinyl pyrrolidone was prepared using the sol-gel method. Investigations were conducted using X-ray diffractometry (XRD), Fourier transformation infrared (FT-IR) spectroscopy. The ionic conductivity and transference number measurements were performed to characterize the polymer electrolyte for battery applications. The transference number data indicated that the conducting species in these electrolytes are the anions. Using the electrolyte, electrochemical cells with a configuration Na/(PVP + NaClO(4))/V(2)O(5) modified by (PVP) were fabricated and their discharge profiles studied.

Chlorates↗
PubMed2005

Preclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone.

PURPOSE: The purpose of our study was to investigate the cellular accumulation, DNA cross-linking ability, and cellular toxicity of RH1 (2,5-diaziridinyl-3-[hydroxymethyl[-6-methyl-1,4-benzoquinone), a novel DNA alkylating agent currently in clinical trials. In addition, the in vivo efficacy of RH1 formulated in different vehicles was also compared. EXPERIMENTAL DESIGN: RH1 is activated by the two-electron reducing enzyme NQO1 [NADPH:quinone oxidoreductase] forming a potent cytotoxic agent that cross-links DNA. We have used whole blood, cell lines, and primary explanted tumor cultures to measure both the cellular accumulation, DNA cross-linking, and cytotoxicity of RH1. Furthermore, the pharmacokinetic and pharmacodynamic characteristics of RH1 formulated in different vehicles were measured in vivo using the validated comet-X assay in mice bearing human tumor xenografts. RESULTS: Accumulation of RH1 was shown to be both time and concentration dependent, reaching a maximum after 2 hours and correlated well with DNA cross-linking measurements. DNA cross-linking in vitro could be detected at low (1-10 nmol/L) concentrations after as little as 2 hours exposure. In primary tumor cultures, RH1 induces much higher levels of DNA cross-links at lower doses than either mitomycin C or cisplatin. In vivo efficacy testing using polyvinyl pyrrolidone, saline, or cyclodextrin as vehicles showed DNA cross-links readily detectable in all tissues examined and was enhanced when given in cyclodextrin compared with polyvinyl pyrrolidone or saline. CONCLUSIONS: RH1 represents a potent bioreductive anticancer drug, which may prove effective in the treatment of cancers, particularly those that overexpress NQO1. DNA cross-linking can be reliably measured in tissue using the validated comet-X assay.

Animals↗
PubMed1996

In vitro study of percutaneous absorption, cutaneous bioavailability and bioequivalence of zinc and copper from five topical formulations.

Percutaneous absorption and cutaneous bioavailability of zinc and copper from zinc 2-pyrrolidone 5-carboxylate (ZnPC), zinc oxide (ZnO), zinc sulfate (ZnSO4), copper 2-pyrrolidone 5-carboxylate (CuPC) and copper sulfate (CuSO4) were compared using 5 formulations (3 emulsions and 2 ointments) that were applied topically on human skin in vitro. After application for 72 h, percutaneous absorption of zinc from ointments containing ZnO and ZnSO4 was found to be lower than that from a ZnPC-containing emulsion (0.36 and 0.34 versus 1.60% of applied dose). In the case of copper, the flux after a 72-hour treatment period showed that there had been minimal release from CuPC- and CuSO4-containing formulations (approximately 5 ng/cm2/h). All formulations used in this study effected an increase in zinc and copper concentrations in whole skin and epidermis. Bioequivalence of the 5 formulations based on pharmacokinetic results was assessed, and salt and vehicle effects were discussed.

Administration, Topical↗
PubMed2006

Reversible photochromic properties of TiO2-polymer nanocomposites.

Composite films of nanosized TiO2 particles, which contained rutile as the only detected crystal modification, and poly(vinyl alcohol), poly(vinyl pyrrolidone) or poly(4-vinylpyridine) were prepared from aqueous dispersions. During exposure to UV irradiation the nanocomposites comprising poly(vinyl alcohol) or poly(vinyl pyrrolidone) turned blue as a consequence of a partial reduction of TiIV to TiIII. The color intensity increased with increasing TiO2 content and irradiation time. This color did not fade after removal of the UV source in spite of the sensitivity of TiIII to atmospheric oxygen. By contrast, exposure to water caused the nanocomposites to adopt their original colorless appearance. These colorization-decolorization cycles could be repeated more than 10 times without apparent loss of intensity. Due to the small size of the TiO2 nanoparticles (ca. 3 nm), patterned blue structures of high resolution could be created in the polymeric materials, for instance with simple masking methods.

Nanotechnology↗
PubMed1996

Hydrolytic cleavage of pyroglutamyl-peptide bond. II. Effects of amino acid residue neighboring the pGlu moiety.

We studied the susceptibility of the pyrrolidone moiety and the pyroglutamyl-peptide bond at pGlu-X-Ala-Phe-OH (X = Gly, Ala, Tyr, Ile, Pro, His, Lys, Arg, Thr, Ser, Asp, Glu and Trp) to 1 N HCl or 2 M trifluoromethanesulfonic acid at 60 degrees C. Here we describe the rates of the cleavage reaction of the pGlu-X bond, the pyrrolidone ring-opening reaction of the pGlu moiety and the hydrolysate accumulation. The rank order of the susceptibility rates of the cleavage reactions was Ser > Pro, Gly > Arg, Ala, Glu, Thr, Asp > His, Lys > Trp, Tyr, Ile, and that of the ring-opening reaction was Ile > Tyr, Trp > Arg, His, Lys, Asp > Glu > Ala > Pro, Gly > Ser > Thr. The rank order of the half-lives of the model peptides was Pro > Arg, Lys, Ile > His, Glu > Ala, Tyr > Asp > Gly > Ser > Thr. The results indicated that a bulky and sterically hindered side chain of the amino acid residue neighboring the pGlu moiety favors the ring-opening reaction, and retards the decomposition on acid hydrolysis and the cleavage reaction. Thus, the ring-opening and the cleavage reactions were greatly affected by the amino acid residue neighboring the pGlu moiety in the hydrolysis of pGlu-peptides.

Amino Acids↗
PubMed1980

Metabolsim of vasodilator 4-(3,4,5-trimethoxycinnamoyl)-1-(1-pyrrolidinyl)carbonylmethylpiperazine (cinepazide): isolated and identification of metabolites in the rat and man.

Further study on identification of metabolites of cinepazide, 4-(3,4,5-trimethoxycinamoyl)-1-(1-pyrrolidinyl)carbonylmethylpiperazine, in rats and men was carried out. New metabolites of cinepazide in rat urine were 4-[1-[4-(3,4,5-trimethoxycinnamoyl)-piperazinly]acetamidol-1-butanol (M-II), 4-(3,4,5-trimethoxycinnamoyl)-1-[1-(hydroxypyrrolidinyl)]carbonylmerthylpiperazine (M-IV) and 4-[1-[4-(3,4,5-trimethoxycinnamoyl)piperazinyl]acetamidol]-1-butyric acid (M-VI). Structures of two mono-O-demethylated metabolites of cinepazide predicted in the previous paper were assigned as 3-hydroxy-4,5-dimethoxycinnamoyl and 4-hydroxy-3,5-dimethoxycinnamoyl compounds (M-III and M-V) by the FT-NMR spectrometry measured in a mixture of CDC13-C6D6 (1:1, v/v) after methylation with dimethylsulfare-d6. The corresponding pyrrolidone metabolite of cinepazide was undetectable in rat urine. New metabolites of cinepazide in rat feces were found to be 4-(3,5-dihydroxy-phenethylcarbonyl)-1-(1-pyrrolidinyl)carbonylmethylpiperazine (M-VIII) and 4-(3,5-dihydroxycinnamoyl)-1-(1-pyrrolidinyl)carbonylmethylpiperazine (M-IX). Metabolites of cinepazide in human urine were studied by both methods--high performance liquid chromatography and mass spectrometry with ion cluster technique. Unchanged drug was mainly excreted in the urine, and M-VI was the major urinary metabolite. The existence of M-IV and M-V was suggested by high performance liquid chormatography. The corresponding pyrrolidone was also undetectable in human urine.

Animals↗
PubMed1997

Skin permeation of parabens in excised guinea pig dorsal skin, its modification by penetration enhancers and their relationship with n-octanol/water partition coefficients.

Skin penetration of methyl, ethyl, propyl and butyl parabens through excised guinea pig dorsal skin was examined, and effects of the penetration enhancers, l-menthol plus ethanol itself and N-dodecyl-2-pyrrolidone, were observed. Permeability of coefficients of the parabens correlated with n-octanol/water partition coefficients. Addition of 1% l-menthol in 15% ethanol about sixteen times increased the permeability coefficient of methyl paraben, whereas this enhancer decreased that of butyl paraben to about one fifth of the control value. A similar, though weaker, tendency was observed for the effects of 15% ethanol itself. 0.025% suspension of N-dodecyl-2-pyrrolidone increased the permeability coefficient of methyl paraben about seven times, whereas it did not change that of butyl paraben significantly. Therefore, dependency of the permeability coefficients of the parabens on n-octanol/water partition coefficients almost disappeared in the presence of this compound. A spin label study with stratum corneum lipid liposomes revealed that increase of fluidity of the lipid bilayer by these penetration enhancers corresponded with their enhancement effects on skin penetration of methyl paraben. Perturbation of stratum corneum lipid lamella thus seems to be related with their enhancement of the absorption of hydrophilic paraben.

Animals↗
PubMedDate not supplied

Pyrrolidonyl and pyridyl alkaloids in Lymantria dispar.

The occurrence and metabolism of nicotine and related N-containing compounds in body fluids of the gipsy moth were addressed. Thin layer chromatographic studies clearly showed the simultaneous presence of GABA and 2-pyrrolidone but not of GABamide in the larval haemolymph and osmeterial secretion of Lymantria dispar as well as in the corresponding body fluids of the saturniids, Saturnia pavonia and Attacus atlas. Furthermore, feeding and injection experiments using alkylated precursors and combined gas chromatography/mass spectrometry gave evidence of the transformation of 2-pyrrolidone to nicotine and of nicotinic acid to nicotinamide in caterpillars of L. dispar. Based on these results, on the earlier described variation of the secondary-compound patterns of L. dispar during its development, and on literature data, metabolic pathways for the hitherto detected pyridyl and pyrrolidonyl alkaloids in Lymantriidae (and possibly Saturniidae) are proposed.

Alkaloids↗
PubMed1999

N-Methyl-D-aspartate receptor antagonists and the development of tolerance to the discriminative stimulus effects of morphine in rats.

Several reports have indicated that N-methyl-D-aspartate (NMDA) receptor antagonists prevent the development of analgesic tolerance to opiates. Some effects of opiates, such as their discriminative stimulus effects, are known to be more resistant to tolerance induction. In this study, adult male Long-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water (vehicle) using a standard, two-lever fixed ratio 10 schedule of food reinforcement. Subsequently, repeated morphine treatment (20 mg/kg; 14 days b.i.d.) was administered, which induced tolerance-like rightward shifts in the dose-effect curves for both morphine's discriminative stimulus and response rate-suppressing effects. Withdrawal-induced, response rate reductions indicative of behavioral dependence appeared as well. Separate groups were then treated repeatedly with a combination of morphine or its vehicle and one of the following competitive or noncompetitive NMDA antagonists: dizocilpine (0.1 mg/kg i.p.), 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene; 3 and 5.6 mg/kg i.p.), eliprodil (17.3 mg/kg i.p.), or R(+)-3-amino-1-hydroxy-2-pyrrolidone [(+)-HA-966; 10 mg/kg i.p.]. The development of tolerance to morphine's stimulus effects was attenuated by eliprodil and the higher dose of D-CPPene, but not by dizocilpine, the lower dose of D-CPPene, nor R(+)-3-amino-1-hydroxy-2-pyrrolidone. All antagonists prevented the induction of tolerance to morphine's response rate effects. Dizocilpine and D-CPPene (5.6 mg/kg) appeared to prevent the induction of behavioral dependence as well. NMDA antagonists can prevent tolerance to the discriminative stimulus effects of morphine, and perhaps to its behavioral dependence effects, but their site of action on the NMDA receptor complex confers a different ability to do so.

Animals↗
PubMed1999

[A fluorimetric study of the interactions of hydrochloridum berberini with vinylpyrrolidone and beta-cyclodextrin].

The interactions of hydrochloridum berberini with 1-vinyl-2-pyrrolidone and beta-cyclodextrin in aqueous solution were studied by spectrofluorimetric method. The spectral changes were quantitatively investigated. Results showed that the complexation with beta-cyclodextrin resulted in an enhancement of the fluorescence of hydrochloridum berberini whereas 1-vinyl-2-pyrrolidone caused a quenching of the fluorescence. It had been supposed 1:1 complex formation. Specifically, formation constants and the thermodynamic parameters at different temperatures were calculated.

Berberine↗
PubMedDate not supplied

[The effect of neutral polymers on glutamate dehydrogenase activity of mouse liver mitochondria upon administration of endotoxin].

It is shown that neutral polymers administered intraperitoneally to intact animals considerably affect glutamate dehydrogenase activity in the liver cell mitochondria as well as in the supernatant. Of the tested polymers, only polyvinyl methylacetamide and dextran inhibit a decrease in the level of mitochondrial enzyme activity which develops with administration of endotoxin. Polyvinyl pyrrolidone with molecular weight of 100 kDa, polyvinyl methylacetamide, dextran and polyvinyl caprolactam prevent an increase of glutamate dehydrogenase activity in the supernatant in case of endotoxin administration to animals. It is possibly a result of the effect of the mitochondrial structure stabilization by the above polymers. A physiological effect of polyvinyl pyrrolidone revealed as an effect on the activity level of mitochondrial glutamate dehydrogenase and in the supernatant after endotoxin administration to animals, depends on the molecular weight of the polymer.

Animals↗
PubMed1990

Transdermal absorption of radioprotectors using permeation-enhancing vehicles.

Radioprotectors are not currently used clinically due to concerns regarding toxicity and uncertainties regarding tumor protection. Topical radioprotection of skin might find clinical applications with protectors such as WR-2721, but laboratory studies in which protectors have been applied in water have not been promising. We have studied the absorption of 14C-WR-2721 and [14C]cysteine dissolved in skin permeation-enhancing vehicles through the skin of hairless mice and compared the absorption to that in water. Skin concentration of WR-2721 was increased most by dimethylformamide (DMF), but only propylene glycol increased absorption as far as the dermis, as measured by plasma concentration. Skin concentration of cysteine was improved by DMF, 2-pyrrolidone (2-P), and methyl-2-pyrrolidone (M-2-P); only dimethylsulfoxide (DMSO) resulted in increased plasma levels of the protector. Pretreating skin with DMSO before application of WR-2721, irrespective of the vehicle, improved its concentration within the skin. Plasma levels were improved (10 and 12 times) only with 2-P and DMF. Therefore, by choosing the appropriate vehicle, it is possible to breach the barrier of the stratum corneum and enhance the presence of the protector in all layers of the skin.

Administration, Cutaneous↗