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PubMed2005

Chemical encapsulation of rocuronium by synthetic cyclodextrin derivatives: reversal of neuromuscular block in anaesthetized Rhesus monkeys.

BACKGROUND: At present, reversal of neuromuscular block induced by steroidal neuromuscular blocking agents (NMBAs) is achieved by administration of cholinesterase inhibitors. Chemical encapsulation of steroidal NMBAs, such as rocuronium, by a cyclodextrin is a new concept in neuromuscular block reversal. The present study evaluates the capacity of nine synthetic cyclodextrin derivatives (Org 25288, Org 25289, Org 25467, Org 25168, Org 25169, Org 25555, Org 25166, Org 26142, and Org 25969) to reverse constant neuromuscular block of approximately 90%, induced by rocuronium infusion in the Rhesus monkey, using single twitch stimulation. The ability of these cyclodextrin derivatives to reverse neuromuscular block was compared with the reversal of the same neuromuscular block by the commonly used combination of neostigmine and atropine. METHODS: After a bolus injection of rocuronium, continuous infusion was started to reduce twitch contractions to approximately 10% of baseline values. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either one of the nine cyclodextrin derivatives or a combination of neostigmine and atropine was given. RESULTS: Recovery with cyclodextrin derivatives Org 26142 and Org 25969 was faster than after a combination of neostigmine and atropine (P<0.05). Injection of these cyclodextrin derivatives did not affect blood pressure or heart rate. Signs of residual block or recurarization were not observed in any of these experiments. In the experiments in which a combination of neostigmine and atropine was given, two animals showed signs of abdominal discomfort as frequently seen after the administration of neostigmine and significant changes in circulatory variables. CONCLUSIONS: Chemical encapsulation or chelation of rocuronium is a new concept in reversing neuromuscular block induced by rocuronium.

Androstanols↗

PubMed2004

Crystal structure of the supramolecular linear polymer formed by the self-assembly of mono-6-deoxy-6-adamantylamide-beta-cyclodextrin.

Mono-6-deoxy-6-adamantylamide-beta-cyclodextrin-dimethylformamide-15H2O, C53H85NO35.C3H7NO.15H2O, crystallizes in the orthorhombic space group P2(1)2(1)2(1). The adamantyl group is inserted into the cyclodextrin cavity of the adjacent molecule, entering by the side of the secondary hydroxy rim, thus forming a supramolecular linear polymer by self-assembly. Adjacent macrocycles are linked into columns by hydrogen bonds involving the nearest glucose residues, and the structure is further stabilized by their involvement in hydrogen bonding with water molecules which reside in channels surrounding the polymer columns, thus acting as bridges between the cyclodextrin units. The centroid of the adamantyl group lies below the plane formed by the seven glycosidic O atoms of the host cyclodextrin, excluding water molecules from the secondary side of beta-cyclodextrin (beta-CD). Between the adamantyl group and the primary hydroxy rim of the cyclodextrin cavity lies a dimethylformamide molecule, which shields the hydrophobic adamantyl group from the primary hydroxy rim of its carrying beta-CD and excludes water molecules from the primary side of the beta-CD cavity.

Amantadine↗

PubMed1994

Use of cyclodextrin as an agent to induce excretion of Bordetella pertussis antigens.

This paper attempts to provide an explanation for the effect of cyclodextrin on the yield of Bordetella pertussis soluble antigens. It was demonstrated that the addition of cyclodextrin to the synthetic Stainer-Scholte liquid medium enhances the level of the intracellular form of adenylate cyclase (200 kDa) in the supernate. In addition to this effect, it has been reported that cyclodextrin also enhances the levels of two other extracellular proteins, pertussis toxin and filamentous hemagglutinin. As these antigens are structurally different, it seems that the effect of cyclodextrin is not specific. With the use of different buffer systems of well-known action on outer membrane stability it was possible to determine a relationship between the presence of cyclodextrin, destabilisation of the outer membrane and the release of proteins. It was determined that the cyclodextrin did not modify the fluidity of B. pertussis cells but produced a change of outer membrane permeability.

Adenylate Cyclase Toxin↗

PubMed2001

Bacillus subtilis contains a cyclodextrin-binding protein which is part of a putative ABC-transporter.

Bacillus subtilis is able to grow on alpha-, beta- and gamma-cyclodextrins as a carbon source via a yet unknown metabolizing system. Sequence analysis of the B. subtilis genome reveals that the putative yvfK-yvfO operon seems to be involved in cyclodextrin utilization, containing the open reading frame yvfK, now termed cycB. The amino acid sequence derived from the DNA sequence bears high similarities to solute-binding proteins from B. subtilis, as well as to cymE from Klebsiella oxytoca and malE from Escherichia coli, both encoding solute-binding proteins able to interact with cyclodextrins. A [His](6)-tagged variant of CycB from B. subtilis was constructed, overproduced in E. coli and purified. The modified protein has been used to study its substrate specificity by surface plasmon resonance and fluorescence spectroscopy. From these data, CycB can be classified as a cyclodextrin-binding protein which interacts with all three natural cyclodextrins: alpha, beta and gamma, thereby showing the highest affinity to gamma-cyclodextrin.

ATP-Binding Cassette Transporters↗

PubMed2005

Dose-dependent inhibition of the post-prandial glycaemic response to a standard carbohydrate meal following incorporation of alpha-cyclodextrin.

BACKGROUND: This study evaluated the dose-response effects of alpha-cyclodextrin, a cyclic oligosaccharide, on the glycaemic and insulinaemic responses to the consumption of a standard carbohydrate meal. METHODS: In a double-blind, randomised, cross-over design, 10 healthy subjects consumed boiled white rice containing 50 g of digestible carbohydrate to which 0 (control), 2, 5 or 10 g of alpha-cyclodextrin was added. Plasma glucose and insulin concentrations were determined prior to and for 2 h after consumption of each meal. RESULTS: The area under the plasma glucose curve was negatively related to the dose of alpha-cyclodextrin (r(2)=0.97, p=0.02), with the areas being significantly reduced at the 5- and 10-gram doses compared with the control (p<0.05). alpha-Cyclodextrin did not affect the area under the plasma insulin curve (p=0.39). Higher doses of alpha-cyclodextrin resulted in greater satiety, but were associated with reduced palatability and an increased incidence of minor gastrointestinal complaints (stomach ache, nausea, bloating). CONCLUSION: alpha-Cyclodextrin reduces the glycaemic response to a standard carbohydrate meal in a dose-dependent manner and may be useful as an ingredient for reducing the glycaemic impact of such foods.

Adult↗

PubMed2006

Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy.

BACKGROUND: Voriconazole was introduced for the treatment of life-threatening fungal infections. The intravenous form includes the solvent vehicle sulphobutylether beta cyclodextrin sodium which shows an impaired clearance under intermittent dialysis therapy. This investigation aimed to determine first clinical data on sulphobutylether beta cyclodextrin sodium blood levels to verify the risk for accumulation. METHODS: In four patients suffering from renal insufficiency and intermittent dialysis therapy who needed a treatment with intravenous voriconazole as a reserve antifungal at the intensive care unit of the Mainz University Hospital the trough levels of voriconazole and sulphobutylether beta cyclodextrin sodium were measured. RESULTS: A 75-year-old woman showed a maximal sulphobutylether beta cyclodextrin sodium plasma level of 145 microg/ml in the initial phase. After a few days renal function recovered and the plasma levels came down to less than 20 microg/ml. In contrast to this patient with a recovery of renal function the remaining three patients showed renal failure during the complete period of intravenous treatment with voriconazole. In these patients an accumulation of sulphobutylether beta cyclodextrin sodium plasma levels was determined with a maximum of 523 mug/ml in a 18-year-old man, 409 microg/ml in a 57-year-old man, and 581 microg/ml in a 47-year-old man. CONCLUSION: The present data indicate an accumulation of sulphobutylether beta cyclodextrin sodium in patients treated with intravenous voriconazole and dialysis therapy. Fortunately, no toxic effects were observed, although the accumulated dose values were lower but comparable with those used in previous toxicity studies with animals.

Aged↗

PubMed2005

Effect of 4-sulphonato-calix[n]arenes and cyclodextrins on the solubilization of niclosamide, a poorly water soluble anthelmintic.

The present study investigated the effect of water-soluble 4-sulphonato-calix[n]arenes, cyclodextrins, and combinations of these macromolecules on the aqueous solubility of a poorly water-soluble drug, niclosamide. Complexation between the macromolecules and niclosamide was confirmed by thermal analysis and phase solubility studies in a pH 7.0 Mcllvaine buffer kept at 30 degrees C. Results show that the increase in solubility ranked as follows: 4-sulphonato-calix[6]arene + hydroxypropyl-beta-cyclodextrin (HP-beta-CD) > 4-sulphonato-calix[6]arene + beta-cyclodextrin > 4-sulphonato-calix[6]arene + gamma-cyclodextrin = HP-beta-CD > 4-sulphonato-calix[6]arene > 4-sulphonato-calix[8]arene = 4-sulphonato-calix[4]arene > beta-cyclodextrin . Type B phase solubility profiles were observed, indicating a decrease in solubility at concentrations > 0.004 to 0.005 mol/L of the 4-sulphonato-calix[n]arenes or combinations of 4-sulphonato-calix[6]arene and the cyclodextrins. However, below this concentration, the greatest increase in the aqueous solubility niclosamide was observed when 4-sulphonato-calix[6]arene and HP-beta-CD were combined. This increase in solubility was additive.

Anthelmintics↗

PubMed1998

Binding, molecular mechanics, and thermodynamics of cyclodextrin inclusion complexes with ketoprofen in aqueous medium.

The purpose of this work was to study the interaction forces involved in the inclusion processes of ketoprofen with several cyclodextrins and to assess the best cyclodextrin for complexing this anti-inflammatory drug. The behavior of the inclusion complexes of ketoprofen with alpha-, beta-, and gamma-cyclodextrins was studied by UV-VIS direct spectroscopy, 1H NMR, and molecular mechanics. Thermodynamic parameters for the binding processes were obtained from the temperature variations in binding constants, which manifest that "nonclassical" hydrophobic interactions are the main forces involved in these inclusion processes. Binding constants show that beta- and gamma-cyclodextrins form more stable 1:1 complexes with ketoprofen than does alpha-cyclodextrin. 1H NMR spectra show that the inclusion degree depends on the size of the internal diameter of cyclodextrin. The geometries calculated on the bases of molecular mechanics for these three-dimensional models indicate high stability.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Effect of cyclodextrins on the solubility and stability of a novel soft corticosteroid, loteprednol etabonate.

To increase the aqueous solubility and stability of the soft corticosteroid loteprednol etabonate (LE), drug complexation using various cyclodextrins (CDs), such as gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HPBCD), maltosyl-beta-cyclodextrin (MBCD), mixture of glucosyl/maltosyl-alpha-, beta-, and gamma-cyclodextrin (GMCD), and heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DMCD), were attempted. The solubilizing and stabilizing effects of CD by itself or combined with various co-solvents were also investigated. Micronized (5 micron) LE was mixed in various aqueous CD or CD with cosolvent solutions. After equilibration and filtration at 23 degrees C, the solubility of LE was determined by HPLC. Subsequently, the stability of LE in the solutions was also determined by following the LE concentration change in the solution for an appropriate period. CD complexation significantly increased the aqueous solubility and stability of LE. The increase in solubility displayed a concentration dependency on CDs (0-50%). Among the five CDs used, DMCD showed the highest effects on the solubility (4.2-18.3 mg/ml in 10-50% DMCD) and stability (t90 > 4 years at 4 degrees C, when LE 0.5 mg/ml was dissolved in 10% DMCD solution) of LE. By adding co-solvents, such as glycerol, propylene glycol (PG), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP-10), the solubility of LE in DMCD solutions was further increased. Degradation of LE to the corresponding metabolites, delta 1-cortienic acid etabonate (AE) and delta 1-cortienic acid (A), in aqueous CD solutions appeared to be a predicted, two-step kinetics. Differential Scanning Calorimetry (DSC) was used to assist explaining the solubilizing and stabilizing activity differences between CDs. LE/CD mixture or lyophilized LE/CD complex was scanned at a rate of 20 degrees C/min. The exothermic peak found in the DSC diagram with LE/DMCD sample, but not with LE/HPBCD samples, suggests a stronger complex formed between LE and DMCD, resulting in higher solubility and stability of LE in DMCD than in HPBCD.

Androstadienes↗

PubMed2001

[Use of cyclodextrins in the formulation of polyalkylcyanoacrylate nanoparticles charged with different active ingredients].

Cyclodextrins were used to improve the loading capacity of biodegradable pol(yisobutyl cyanoacrylat)e nanoparticles, which were obtained by anionic polymerization in aqueous medium. We investigated the feasibility of blank nanoparticles in the presence of a series of cyclodextrins (5 mg/ml) and poloxamer 188 (1%). The smaller particles (87 +/- 3 to 103 +/- 6 nm) were obtained in the presence of hydroxypropyl beta- or gamma-cyclodextrin. The nanoparticle loading capacity investigated in the presence of hydroxypropyl beta-cyclodextrin, in the previous conditions, on a series of steroids revealed an increase varying from 5.5 times (megestrol acetate) to 130 times (prednisolone). Differential scanning calorimetry study of the active ingredient (progesterone) in the nanoparticles, revealed an amorphous or molecular state. The in vitro release of the active ingredient occurred very rapidly but reached a plateau depending on the nanoparticle size and the dissolution medium nature. All the active ingredient was released in the presence of esterases. The addition of a preformed hydroxypropyl beta-cyclodextrin/saquinavir inclusion compound to the preparation medium of poly(isobutyl [or] isohexyl cyanoacrylate) nanoparticles, resulted in a 20-fold increase in the encapsulation yield. Presently, poly(isobutyl cyanoacrylate) hydroxypropyl beta-cyclodextrin combined nanoparticles loaded with doxorubicin are in phase II clinical trials.

Cyanoacrylates↗

PubMed2005

Cyclodextrins: application in different routes of drug administration.

The objective of this review article is to explain the use of cyclodextrin in the different routes of drug administration. The article gives the chemistry of cyclodextrins and addresses the issue of the mechanism of drug release from cyclodextrin complexes. Dilution, competitive displacement, protein binding, change in ionic strength and temperature and drug uptake by tissues are the different release mechanisms of the drug from the drug-cyclodextrin complex discussed here. Use and its limitations in the different drug delivery systems like nasal, ophthalmic, transdermal and rectal drug delivery are explained. The application of the cyclodextrins in the oral drug delivery is detailed in this review. Many studies have shown that cyclodextrins are useful additives in the different routes of drug administration because of increased aqueous solubility, stability, bioavailability and reduced drug irritation.

Administration, Cutaneous↗

PubMed2005

Effects of beta-cyclodextrins on the enzymatical hydrolysis of chiral dichlorprop methyl ester.

The effect of beta-cyclodextrins (beta-CDs) on the enzymatical hydrolysis of chiral dichlorprop methyl ester (DCPPM) was studied. Four kinds of beta-cyclodextrins (beta-cyclodextrin, Partly methylated-CD (PM-beta-CD), hydroxypropyl-cyclodextrin (HP-beta-CD) and carboxymethyl-cyclodextrin (CM-beta-CD)) were used. Compared with 100% DCPPM in the absence of betacyclodextrins, the activity of lipase decreased with the increase of Pbetacyclodextrin and PM-Pbetacyclodextrin. However, CM-beta-clodextrin stimulated the lipase activity. The inhibition effect of Pbeta cyclodextrin and PM-5betacyclodextrin on the hydrolysis of DCPPM is affected by many factors other than degree of the methylation blocking the active site of lipase. UV-Vis and Fourier transform infrared (FTIR) spectroscopy studies of the complexation of aqueous DCPPM with beta-CDs provide fresh insight into the molecular structure of the complex and explain the effects of beta-CDs on enzymatical hydrolysis of chiral DCPPM. Data showed that inclusion complexes had formed by complexation of the CM-beta-CD with DCPPM and the solubility of DCPPM was increased in water, which lead to the increased lipase activity.

2,4-Dichlorophenoxyacetic Acid↗

PubMed2005

Influence of cyclodextrin complexation on piroxicam gel formulations.

The aim of this work was to evaluate the role of cyclodextrins in topical drug formulations. Solid piroxicam (PX) complexes with beta-cyclodextrin (beta-CD) and randomly methylated beta-cyclodextrin (RAMEB) were prepared by freeze-drying and characterized using differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and near infrared spectroscopy (NIR). A physical mixture of PX and cyclodextrins was characterized by enhanced dissolution properties compared to the dissolution profile of the pure drug due to in situ complex formation. Formation of the PX-cyclodextrin inclusion complex additionally improved the drug dissolution properties. Influence of CDs on drug permeation from the water dispersion and the prepared hydroxypropyl methylcellulose (HPMC) gels was investigated. Permeation of the drug involved three consecutive processes: dissolution of the solid phase, diffusion across the swollen polymer matrix and drug permeation through the membrane. Complexation increased PX diffusion by increasing the amount of diffusible species in the donor phase. Slower drug diffusion through the HPMC matrix was the rate limiting step in the overall diffusion process. Possible interaction between the hydrophilic polymer and cyclodextrin may result in physicochemical changes, especially in a change of rheological parameters.

Administration, Topical↗

PubMed2006

Cyclodextrin (CD) complexes of cholesterol--their potential use in reducing dietary cholesterol intake.

The main objective of this investigation was to test and see if cyclodextrins, a type of molecule which form inclusion complexes, could effectively prevent the absorption of food derived cholesterol. Cyclodextrins are nontoxic and easily tolerated, having only a slight sweet taste. alpha,beta,gamma-Cyclodextrins, 2-Hydroxypropyl-beta-cyclodextrin (2-HPCD), and heptakis-O,O-dimethyl-beta-cyclodextrin (DMCD) were tested in solutions of different concentrations. These solutions were then saturated with cholesterol and the excess cholesterol was removed. The clear solutions left were then analyzed by HPLC to assess the amount of cholesterol in the solutions, and compared to a standard. DMCD gave the best results in successfully dissolving (complexing) most of the cholesterol followed by HPCD and alpha-cyclodextrin. Beta- and gamma-CD showed nearly insignificant complex formation. After administration of 10 mg of cholesterol to mice through a gastric tube, the cholesterol level increased about 125-130%, and only 15-20%, if the cholesterol was administered together with 20 mg of DMCD. That means, the DMCD formed complexes with approximately 80-85% of the cholesterol administered in the mice gastrointestinal tract.

Animals↗

PubMedDate not supplied

The potential use of cyclodextrins in parenteral formulations.

The general use of cyclodextrins in drug formulations is reviewed. The ability of cyclodextrins to form reversible inclusion complexes with many drugs can eliminate various undesirable physicochemical properties. While beta-cyclodextrin is extremely useful in many of these applications, it is toxic when given parenterally, precluding its use in i.v. and other formulations. Chemically modified cyclodextrins such as 2-hydroxypropyl-beta-cyclodextrin are amorphous isomeric mixtures which are potent complexing agents and innocuous when administered i.e., either acutely or subchronically. The use of these modified cyclodextrins in parenteral formulations and to solubilize and stabilize various proteins and peptides is presented.

Chemical Phenomena↗

PubMed2005

Removal of polycyclic aromatic hydrocarbons from aged-contaminated soil using cyclodextrins: experimental study.

The removal of polycyclic aromatic hydrocarbons (PAHs) from soil using water as flushing agent is relatively ineffective due to their low aqueous solubility. However, addition of cyclodextrin (CD) in washing solutions has been shown to increase the removal efficiency several times. Herein are investigated the effectiveness of cyclodextrin to remove PAH occurring in industrially aged-contaminated soil. Beta-cyclodextrin (BCD), hydroxypropyl-beta-cyclodextrin (HPCD) and methyl-beta-cyclodextrin (MCD) solutions were used for soil flushing in column test to evaluate some influent parameters that can significantly increase the removal efficiency. The process parameters chosen were CD concentration, ratio of washing solution volume to soil weight, and temperature of washing solution. These parameters were found to have a significant and almost linear effect on PAH removal from the contaminated soil, except the temperature where no significant enhancement in PAH extraction was observed for temperature range from 5 to 35 degrees C. The PAHs extraction enhancement factor compared to water was about 200.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2003

Enhancement of the fluorescence and stability of o-phthalaldehyde-derived isoindoles of amino acids using hydroxypropyl-beta-cyclodextrin.

Addition of hydroxypropyl-beta-cyclodextrin to o-phthalaldehyde (OPA)-amino acid-thiol reaction mixtures is shown to cause significant enhancement of the fluorescence of the isoindole product for a wide range of amino acids, with the largest effects observed in the cases of glycine and lysine. The largest enhancement observed was a factor of 2.67 in the case of the derivative of glycine. This fluorescence enhancement is the result of the formation of a 1:1 host:guest inclusion complex between the isoindole and the cyclodextrin. Relatively small association constants of 44 and 130 M(-1) were obtained for the inclusion of the derivatives of glycine and lysine, respectively. Inclusion of the isoindole derivative into hydroxypropyl-beta-cyclodextrin was also found to result in a significant stabilization of the isoindole derivatives, contrary to what has been previously reported for inclusion into beta-cyclodextrin. For example, the lifetime of the lysine derivative was found to increase from 42 to 222 min, a factor of 5.3. These results have potential applications in fluorescence-based HPLC and high-performance capillary electrophoresis amino acid analysis methods using OPA derivation. Addition of hydroxypropyl-beta-cyclodextrin to the reaction mixture results in an increase in both the fluorescence and the stability of the isoindole product, providing potentially significant improvements to the method.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1996

Modulation of oligonucleotide-induced immune stimulation by cyclodextrin analogs.

Some phosphorothioate oligonucleotides have been shown previously to stimulate cell proliferation and immunoglobulin production. In the current study, we examined the effects of cyclodextrin analogs as immunomodulatory agents for oligonucleotide-induced immune stimulation, both in vitro and in vivo. Incubation of splenocytes with a 27-mer phosphorothioate oligonucleotide that induces immune stimulation increased cell proliferation as measured by [3H]thymidine incorporation, whereas treatment of splenocytes with the phosphorothioate oligonucleotide complexed to cyclodextrin analogs markedly reduced oligonucleotide-induced cell proliferation. Similarly, administration of the 27-mer phosphorothioate oligonucleotide into mice resulted in splenomegaly and an increase in IgM production 48 hr post-administration. Administration of the oligonucleotide along with cyclodextrin analogs resulted in a significant suppression of splenomegaly and IgM response. Such suppression was dependent on the concentration of cyclodextrin analogs and was observed with various other immune stimulatory phosphorothioate oligonucleotide sequences. Administration of cyclodextrin analogs alone had no effect on splenomegaly or immune stimulation.

2-Hydroxypropyl-beta-cyclodextrin↗