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PubMed1992

Interactions between epidurally and intrathecally administered sufentanil and bupivacaine in hydroxypropyl-beta-cyclodextrin in the rat.

The interaction between inactive doses of the opioid sufentanil and the local anesthetic bupivacaine after complexation in various concentrations of hydroxypropyl-beta-cyclodextrin (HP-B-CD) were studied after epidural and intrathecal administration in the rat. Whereas 0.125 microgram sufentanil and 80 micrograms bupivacaine produced only limited effects, a combination of the two compounds resulted in a profound surgical analgesia in all rats tested after epidural administration. Also intrathecally, a clear potentiation was present. The complexation of the same doses of sufentanil plus bupivacaine in HP-B-CD increased the duration of analgesia. Epidurally, a maximal potentiation of analgesia was present at 0.125 microgram sufentanil plus 80 micrograms bupivacaine in 20% HP-B-CD. Intrathecally, maximal potentiation of the analgesic activity was present starting from a complexation of both drugs in 10% hydroxypropyl-beta-cyclodextrin. Higher concentrations of hydroxypropyl-beta-cyclodextrin did not significantly further increase the duration of analgesia. These results indicate that for both routes of spinal administration, the complexation of sufentanil plus bupivacaine in HP-B-CD can produce a longer analgesia than either plain sufentanil, sufentanil combined with bupivacaine or sufentanil alone in HP-B-CD. The complexation of sufentanil plus bupivacaine in HP-B-CD did not diminish the increased safety observed to occur after complexation of sufentanil in HP-B-CD and after combination of sufentanil plus bupivacaine.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1997

The Effect of Sodium Dodecyl Sulfate and M-alpha-Cyclodextrin on the Solubility and Partitioning of Xylenes in Aqueous Solutions

The solubility and the partitioning of p- and o-xylene in aqueous solutions containing M-alpha-CD, a partially methylated alpha-cyclodextrin, and the anionic surfactant sodium dodecyl sulfate (SDS) were studied by extraction experiments to evaluate the applicability of liquid membrane permeation for the separation of xylene isomeres. Experiments were carried out with the pure xylenes and 1:1 mixtures of o- and p-xylene. The interactions of M-alpha-CD and SDS and their effects on the solubility and partitioning of xylenes were investigated. M-alpha-CD was found to form 1:1 complexes with p- and o-xylene. Formation constants were determined as 141 M-1 for p-xylene and 48 M-1 for o-xylene, respectively, which are higher than those reported with nonmethylated alpha-CD. This can be explained by additional hydrophobic interactions with the methyl groups of the cyclodextrin. In contrast to the solubility in CD solutions, o-xylene was found to be more soluble than p-xylene in aqueous solutions of SDS. At constant concentrations of M-alpha-CD the addition of SDS led to the displacement of p-xylene from the cyclodextrin cavity, which resulted in a decrease in its solubility. This decrease lasted until micelles were formed. Due to the solubilization of p-xylene in the micelles, further addition of SDS resulted in a linear increase in the solubility of p-xylene. However, at constant CD concentrations the solubility of o-xylene increased with the addition of SDS until about 5 mmol/liter SDS. This might be attributed to the formation of a ternary complex consisting of cyclodextrin, o-xylene, and SDS. At SDS concentrations greater than 5 mmol/liter, the solubility of o-xylene decreased, which was probably due to the formation of a more stable complex between SDS and M-alpha-CD. An addition of SDS beyond a critical concentration (CMC), where micelles are formed, resulted again in a linear increase of o-xylene solubility. The CMC was found to depend linearly on the concentration of M-alpha-CD in aqueous solution. Extraction experiments with a 1:1 mixture of o- and p-xylene showed that the two xylenes and SDS are in competition for M-alpha-CD. Since surfactants are always present when using emulsion liquid membranes and due to the complex interactions between SDS, the xylenes, and M-alpha-CD, no sufficient selectivity for the separation of the xylenes by liquid membrane permeation could be achieved.

Journal Article↗
PubMed1999

Drug-Cyclodextrin Association Constants Determined by Surface Tension and Surface Pressure Measurements.

The complexation reaction between the amphiphilic peptide antibiotic polymyxin B and naturally occurring cyclodextrins, used as potential drug carriers, was quantitatively evaluated from surface tension measurements at various drug concentrations. The association constant, Ka, of polymyxin B:beta-cyclodextrin inclusion complex formation of 1:1 stoichiometry was determined from the change in the drug interfacial activity upon the addition of beta-cyclodextrin at the excess solution concentration (10(-3) M). The obtained Ka value is discussed in terms of molecular matching of the host cyclodextrin cavity and the guest drug molecule. Copyright 1999 Academic Press.

Journal Article↗
PubMed1988

Microcalorimetric and chromatographic investigations of the binding of some pyridine derivatives to cyclodextrins.

The binding of some pyridine derivatives to alpha-, beta- and gamma-cyclodextrins has been investigated by microcalorimetry. The strongest binding is to beta-cyclodextrin, but the binding constants are of the order 10(2) M(-1). The binding to beta-cyclodextrin was also investigated by high performance liquid chromatography. The addition of beta-cyclodextrin to the mobile phase allowed separation of molecules with similar binding constants and of racemates in the case of tropicamide.

Journal Article↗
PubMed2003

CymA of Klebsiella oxytoca outer membrane: binding of cyclodextrins and study of the current noise of the open channel.

CymA, the outer membrane component of the cyclodextrin (CD) uptake and metabolism system of Klebsiella oxytoca, was reconstituted into lipid bilayer membranes. The channel properties of this unusual porin were studied in detail. The binding of CDs to the channel resulted in its complete block for ion transport. This result allowed the detailed investigation of carbohydrate binding, and the stability constants for the binding of cyclic and linear carbohydrates to the binding site inside the channel were calculated from titration experiments of the membrane conductance with the carbohydrates. Highest stability constant was observed for alpha-cyclodextrin (alpha-CD; K = 32,000 1/M) followed by beta-cyclodextrin (beta-CD; K = 1970 1/M) and gamma-cyclodextrin (gamma-CD; K = 310 1/M). Linear maltooligosaccharides bound also to CymA but with much smaller stability constants as compared to cyclic ones. The noise of the current through CymA in multi- and single-channel experiments was investigated using fast Fourier transformation. The current through the open channels had a rather high spectral density, which was a Lorentzian function of the frequency up to 2000 Hz. Upon addition of cyclic dextrins to the aqueous phase the spectral density decreased in a dose-dependent manner, which made it impossible to evaluate the binding kinetics. Experiments with single CymA-channels demonstrated the channel is highly asymmetric concerning channel flickers and current noise.

Bacterial Proteins↗
PubMed2001

Purification and properties of a novel raw starch degrading-cyclodextrin glycosyltransferase from Klebsiella pneumoniae AS- 22.

A novel raw starch degrading alpha-cyclodextrin glycosyltransferase (CGTase; E.C. 2.4.1.19), produced by Klebsiella pneumoniae AS-22, was purified to homogeneity by ultrafiltration, affinity and gel filtration chromatography. The specific cyclization activity of the pure enzyme preparation was 523 U/mg of protein. No hydrolysis activity was detected when soluble starch was used as the substrate. The molecular weight of the pure protein was estimated to be 75 kDa with SDS-PAGE and gel filtration. The isoelectric point of the pure enzyme was 7.3. The enzyme was most active in the pH range 5.5-9.0 whereas it was most stable in the pH range 6-9. The CGTase was most active in the temperature range 35-50 degrees C. This CGTase is inherently temperature labile and rapidly loses activity above 30 degrees C. However, presence of soluble starch and calcium chloride improved the temperature stability of the enzyme up to 40 degrees C. In presence of 30% (v/v) glycerol, this enzyme was almost 100% stable at 30 degrees C for a month. The K(m) and k(cat) values for the pure enzyme were 1.35 mg ml(-1) and 249 &mgr;M mg(-1) min(-1), respectively, with soluble starch as the substrate. The enzyme predominantly produced alpha-cyclodextrin without addition of any complexing agents. The conditions employed for maximum alpha-cyclodextrin production were 100 g l(-1) gelatinized soluble starch or 125 g l(-1) raw wheat starch at an enzyme concentration of 10 U g(-1) of starch. The alpha:beta:gamma-cyclodextrins were produced in the ratios of 81:12:7 and 89:9:2 from gelatinized soluble starch and raw wheat starch, respectively.

Journal Article↗
PubMed1999

Cyclodextrins in targeting. Application to nanoparticles.

For some years cyclodextrins and their hydrophilic derivatives have been described in the literature as solubilizers capable of enhancing the loading capacity of liposomes and microparticles. We present here two new possibilities of using cyclodextrins in the design of colloidal carriers. The first possibility consists in increasing the loading capacity of poly(isobutyl cyanoacrylate) nanospheres prepared by anionic polymerization, by employing hydroxypropyl cyclodextrins. The second possibility consists in the spontaneous formation of either nanocapsules or nanospheres by the nanoprecipitation of amphiphilic cyclodextrin diesters. These two new techniques are very promising because of the great interest presented by nanoparticles for drug administration by the oral or parenteral routes.

Journal Article↗
PubMed1994

Four aromatic residues in the active center of cyclodextrin glucanotransferase from alkalophilic Bacillus sp. 1011: effects of replacements on substrate binding and cyclization characteristics.

Three-dimensional structures of cyclodextrin glucanotransferases (CGTases) have revealed that four aromatic residues, which are highly conserved among CGTases but not found in alpha-amylases, are located in the active center. To analyze the roles of these aromatic residues, Phe-183, Tyr-195, Phe-259, and Phe-283 of Bacillus sp. 1011 CGTase were replaced by site-directed mutagenesis, and the effects of this procedure were examined. Y195L-CGTase, in which Tyr-195 was replaced by a leucine residue, underwent a drastic change in its cyclization characteristics: it produced considerably more gamma-cyclodextrin than the wild-type enzyme and virtually no alpha-cyclodextrin. Y195L-CGTase had increased Km values for cyclodextrins, whereas the values for a linear maltooligosaccharide donor were insignificantly changed. Taken together with the structural information of CGTase crystals soaked with substrates, we propose that Tyr-195 plays an important role in the spiral binding of substrate. Replacing either Phe-183 or Phe-259 with leucine induced increased Km values for acceptors. Furthermore, the double mutant F183L/F259L-CGTase had considerably decreased cyclization efficiency, but the intermolecular transglycosylation activity remained normal. These results indicated that Phe-183 and Phe-259 are cooperatively involved in acceptor binding, and that they play a critical role in cyclization when the nonreducing end of amylose binds to the active center of CGTase. Replacing Phe-283 with a leucine residue induced a decrease in kcat and in affinity for acarbose, suggesting that Phe-283 is involved in transition-state stabilization.

Acarbose↗
PubMedDate not supplied

Immobilization and stabilization of a cyclodextrin glycosyltransferase by covalent attachment on highly activated glyoxyl-agarose supports.

Covalent immobilization of cyclodextrin glycosyltransferase on glyoxyl-agarose beads promotes a very high stabilization of the enzyme against any distorting agent (temperature, pH, organic solvents). For example, the optimized immobilized preparation preserves 90% of initial activity when incubated for 22 h in 30% ethanol at pH 7 and 40 degrees C. Other immobilized preparations (obtained via other immobilization protocols) exhibit less than 10% of activity after incubation under similar conditions. Optimized glyoxyl-agarose immobilized preparation expressed a high percentage of catalytic activity (70%). Immobilization using any technique prevents enzyme inactivation by air bubbles during strong stirring of the enzyme. Stabilization of the enzyme immobilized on glyoxyl-agarose is higher when using the highest activation degree (75 micromol of glyoxyl per milliliter of support) as well as when performing long enzyme-support incubation times (4 h) at room temperature. Multipoint covalent immobilization seems to be responsible for this very high stabilization associated to the immobilization process on highly activated glyoxyl-agarose. The stabilization of the enzyme against the inactivation by ethanol seems to be interesting to improve cyclodextrin production: ethanol strongly inhibits the enzymatic degradation of cyclodextrin while hardly affecting the cyclodextrin production rate of the immobilized-stabilized preparation.

Enzymes, Immobilized↗
PubMed2006

Linear polypseudorotaxanes possessing many metal centers constructed from inclusion complexes of alpha-, beta-, and gamma-cyclodextrins with 4,4'-dipyridine.

Three cyclodextrin-based complexes, 1-3, bearing external coordination sites for metal cations were prepared in satisfactory yields (over 50%) by reactions of alpha-, beta-, and gamma-cyclodextrins with 4,4'-dipyridine in aqueous solutions. Subsequently, these inclusion complexes were further assembled to form linear polypseudorotaxanes 4-6 through the coordination linkage of Ni(II) or Cu(II) ions, and their assembly behaviors were comprehensively investigated in both solutions and the solid state by means of 1H NMR, FT-IR, UV-vis spectroscopy, conductivity titration, powder X-ray diffraction patterning, thermogravimetric and differential thermal analysis, scanning electron microscopy, scanning tunneling microscopy, and transmission electron microscopy. The results showed that these polypseudorotaxanes existed as individual linear arrays at a low concentration but tended to form polymeric rodlike fibers at a relatively high concentration. Significantly, the volume of the cyclodextrin cavity used not only determined the inclusion complexation stoichiometry between cyclodextrin and 4,4'-dipyridine but also predominated the morphology of resulting polypseudorotaxanes.

Journal Article↗
PubMed2001

Effect of cyclodextrin on the intramolecular catalysis of amide hydrolysis.

The hydrolysis reaction of phthalamic acids (HOOCArCONHR, R = p-NO(2)Ph 1a, Ph 1b, adamantyl 1c) and N-phenyl maleamic acid 2b was studied in the presence of hydroxypropyl-beta-cyclodextrin (HPCD) in acid solution. The reactions of 1a and 1b were studied also in the presence of beta-cyclodextrin (beta-CD). All the compounds formed inclusion complexes with HPCD, and the association constant was determined from the change in absorption of the substrate when the host is added in the case of 1a (90 M(-)(1)) and 2b (49 M(-)(1)). For 1c ( 4 x 10(4) M(-)(1)) a competition method was used, and for 1b the association equilibrium constant was obtained from the kinetic data (37 M(-)(1)) because it is too reactive for the spectrophotometric method. Both cyclodextrins strongly inhibited the reactions, and analysis of the kinetic data for HPCD indicated that the reactions of complexed 1a, 1b, and 2b are at least 10-30 times slower than in the bulk solution whereas 1c reacts only 4.6 times slower when it is complexed. The inhibition is attributed to changes in the geometry of the substrate due to interaction of the carboxylic group and/or the amide with the OH at the rim of the cyclodextrin. The differences in the relative effect observed for 1c are attributed to the formation of a tighter complex with this substrate.

Journal Article↗
PubMed2000

Supramolecular photochirogenesis. 2. Enantiodifferentiating photoisomerization of cyclooctene included and sensitized by 6-O-modified cyclodextrins

Supramolecular enantiodifferentiating photoisomerization of (Z)-cyclooctene (1Z) to the chiral (E)-isomer (1E) via inclusion and sensitization by modified alpha-, beta-, and/or gamma-cyclodextrin derivatives, possessing benzoate (2a, 3a, 4a), isomeric phthalates (3b-d), and tethered benzamide (3e) chromophores, has been investigated in aqueous methanol solutions at varying temperatures. The photostationary-state 1E/1Z ratios obtained upon sensitization with 2-4 in 1:1 water-methanol reached 0.4-0.8, which are higher than the value of ca. 0.25 reported for sensitizations by conventional alkyl benzoates in hydrocarbon solvents, although the ratio was reduced to 0.2-0.4 in water or methanol. The sensitizations of 1Z by alpha- and gamma-cyclodextrin benzoates (2a, 4a) with size-mismatched cavities gave 1E of poor enantiomeric excesses (ee's) smaller than 3 and 5%, respectively. In contrast, beta-cyclodextrin derivatives (3a-e) afforded much higher ee's of up to 24%, depending on the solvent composition. Thus, the modification of cyclodextrin with a sensitizing group successfully enhanced the product through the excited-state supramolecular interaction within the cavity. Interestingly, the product ee's obtained with benzoate 3a and methyl phthalate 3b are not a simple function of either temperature or solvent, but are nicely correlated with the host occupancy or the percentage of occupied host. This means that the entropy factor plays an insignificant role in this supramolecular photochirogenesis system, which is in sharp contrast to the decisive role of entropy in the conventional (nonsupramolecular) counterpart performed in homogeneous solutions, where an inversion of product chirality by temperature variation is reported to occur.

Journal Article↗
PubMed1997

Novel Method to Prepare Dihydroxy Permethylated beta-Cyclodextrin Isomeric Intermediates for Bifunctional Enzyme Mimics.

Natural beta-cyclodextrin was treated with 3.5 equiv of tert-butyldimethylsilyl chloride and then with NaH and MeI in the same reaction vessel to give a mixture of oligosilyl-substituted permethylated beta-cyclodextrins. The mixture was treated with NH(4)F and the resulting 6(A),6(D)-(1), 6(A),6(C)-(2), and 6(A),6(B)-(3) dihydroxy permethylated beta-cyclodextrins were isolated in 7.6-8.9% yields by two silica gel chromatographic separations. The structures of 1-3 were verified by comparison of spectral properties with a known diol (2) or preparing known derivatives (1 and 3). This is a superior way to prepare and isolate dihydroxy permethylated beta-cyclodextrin intermediates for bifunctional enzyme mimics.

Journal Article↗
PubMed2005

High conversion synthesis of pyrene end functionalized polyrotaxane based on poly(ethylene oxide) and alpha-cyclodextrins.

We describe the quantitative synthesis of new pyrene labeled cyclodextrin-based polyrotaxane starting from pseudopolyrotaxane of alpha,omega-dimethacrylate poly(ethylene oxide) (PEO) and alpha-cyclodextrins (alpha-CDs). Using a solvent mixture (H2O/dimethyl sulfoxide (DMSO)), an almost quantitative conversion in polyrotaxane can be achieved using the coupling reaction between methacrylic functions and 1-pyrene butyric acid N-hydroxysuccinimide ester. This result is due to the fast blocking reaction of the pseudopolyrotaxane telechelic functions. The polyrotaxanes are characterized by NMR, size exclusion chromatography (SEC), and small-angle neutron scattering (SANS). A rodlike structure of the polyrotaxane is evidenced by SANS, and a persistence length of 70 A is determined. This result corresponds to an almost completely stretched PEO chain of 1000 g.mol(-1) molecular weight. We furthermore studied the opposite case of low packing density polyrotaxanes that were also silylated to suppress interactions between cyclodextrins. We observed a random coil structure only for silylated low packed polyrotaxane. This result demonstrates that both hydrogen bonding and packing density can explain the rodlike structure of cyclodextrin-based polyrotaxane.

Journal Article↗
PubMed2006

pH dependent in-out isomerism of an amino-beta-cyclodextrin derivative.

An amino derivative of beta-cyclodextrin [6-(6-aminehexanamide)-6-deoxy)-beta-cyclodextrin (6-betaCD)] was synthesized, and the formation of an intramolecular inclusion complex was studied by NMR techniques. The deprotonation/protonation of the amino group stimulates an in/out movement of the pendant group toward/from the cyclodextrin cavity, the protonated species lying outside the hydrophobic cyclodextrin cavity but the unprotonated one residing inside and outside the cavity. The protonation of the amino group is a fast exchange rate NMR time-scale process, but the chain movement is a slow one. The equilibrium constants of both processes were determined from 1H NMR experiments and the kinetic constants for the slow process were determined from exchange spectroscopy (EXSY) experiments.

Journal Article↗
PubMed2004

Determination of the enantiomeric composition of phenylalanine samples by chemometric analysis of the fluorescence spectra of cyclodextrin guest-host complexes.

A novel strategy for determining the enantiomeric composition of phenylalanine samples that combines ordinary fluorescence spectroscopy, guest-host cyclodextrin chemistry, and multivariate regression modeling is investigated. Partial-least-squares regression (PLS-1) models were developed from fluorescence spectral data obtained with a series of samples containing cyclodextrin guest-host complexes of phenylalanine with different known enantiomeric compositions. The regression models were subsequently validated by determining the enantiomeric composition of a set of independently prepared phenylalanine samples. The ability of the models to correctly predict the enantiomeric compositions of future samples was evaluated in terms of the root-mean-square percent relative error (RMS%RE). The RMS%RE in the mol fraction of D-phenylalanine ranged from 1.3% to 3.0% when beta-cyclodextrin was used as the host molecule for different guest-host concentrations. The RMS%RE in the mol fraction of D-phenylalanine obtained in a similar validation study conducted with gamma-cyclodextrin ranged between 1.8% and 4.0% for different guest-host concentrations. Compared with previous studies done in absorption, fluorescence data were found to be more sensitive and the spectral differences observed as a function of enantiomeric composition were more uniformly spaced, making regression modeling more reliable. As a result, good regression models could be made at lower concentrations than were possible previously when absorption measurements were used.

Isomerism↗
PubMed2003

Analytic quantification of solar lentigines lightening by a 2% hydroquinone-cyclodextrin formulation.

BACKGROUND: The innate melanin pigmentation of skin is modulated during lifetime by a series of factors, including ageing and chronic ultraviolet light exposure. Actinic lentigines may be of particular concern from a cosmetic point of view. Conventional hypopigmenting agents are usually deceptive. Using cyclodextrins to form inclusion compounds with these agents might represent a more active drug delivery system. OBJECTIVE: To assess sensitive and objective methods predicting the effects of a 2% hydroquinone-cyclodextrin formulation on solar lentigines. STUDY DESIGN: Thirty Asian adults applied a 2% hydroquinone-cyclodextrin formulation once daily on solar lentigines of a forearm for 2 months. The other untreated forearm served as a control. Monthly assessments were performed using skin colorimetry and fluorescence video recording combined with image analysis. Corneomelametry following photodensitometry of cyanoacrylate skin surface strippings was performed after melanin staining of the samples. RESULTS: The control untreated solar lentigines showed no significant variations in the biometrological parameters. By contrast, the test formulation induced lightening of the solar lentigines. Corneomelametry disclosed improvement after 1 months' treatment, whereas the other assessments only reached significance after 2 months. CONCLUSIONS: A 2% hydroquinone-cyclodextrin formulation proved to be effective in lightening actinic lentigines. Corneomelametry predicted the effects discernible at a later stage by in vivo colour assessments of the melanin content.

Administration, Topical↗
PubMed1976

Amine-catalyzed hydrolyses of cyclodextrin cinnamates.

Hydrolyses of beta-cyclodextrin cinnamate (betaCDC) and alpha-cyclodextrin cinnamate were catalyzed by amines such as 1,4-diazabicyclo(2.2.2)octane, triethylamine, quinuclidine, piperidine, diisobutylamine, and n-butylamine. The rate constant of hydrolyses of the betaCDC-amine complexes follows the order: 1,4-diazabicyclo(2.2.2)octane > n-butylamine > quinuclidine > piperidine > triethylamine >> diisobutylamine. The ratio of the catalytic rate constant for the betaCDC/1,4-diazabicyclo(2.2.2)octane complex to the spontaneous rate constant for betaCDC is about 6-fold and is almost independent of pH below pH 11.5; but, it then drastically increases with pH above pH 11.5, up to 57-fold at pH 13.6 which is much higher than previous attempts. The pH-rate constant profile and isotope effect with deuterium oxide solvent indicate that 1,4-diazabicyclo(2.2.2)octane, included in betaCDC, assists the catalytic nucleophilic attack by hydroxide ion toward the carbonyl carbon of betaCDC. Acceleration of deacylation of acyl-cyclodextrins, by amines, has made the cyclodextrin-catalyzed hydrolysis of esters an even better model of hydrolytic enzyme reactions than those developed previously.

Journal Article↗