Kangaroo mother care alters chromogranin A and perfusion index in preterm babies.

BACKGROUND: While providing various benefits, concerns about the potential risks of kangaroo mother care, or skin-to-skin contact (SSC), between mother and her preterm infant hinder its widespread implementation in some resource- rich countries. In neonates, salivary chromogranin A (s-CgA) is elevated upon exposure to stress, whereas the perfusion index (PI) is associated with hemodynamics and peripheral perfusion. Here, we investigated the effects of SSC on s-CgA and the PI in preterm infants. METHODS: Twelve infants were enrolled in the study. Factors associated with baseline s-CgA were analyzed. Baseline s-CgA and the level after SSC were compared. Secreted IgA in the saliva was compared as the control. The PI before, throughout, and after SSC were compared. RESULTS: Baseline s-CgA was significantly lower in infants who were supplemented with baby formula milk in addition to breast milk before SSC (n = 2) compared with those fed with their mother's breast milk alone (n = 10, P = 0.03). SSC significantly decreased s-CgA in babies who were fed breast milk only before SSC (n = 10, P = 0.01) but not in those supplemented with formula milk before SSC (n = 2). Secreted IgA in saliva was not affected by SSC. The PI was significantly elevated during SSC (P = .01). CONCLUSION: Our data indicate that SSC can reduce s-CgA levels when combined with mother's breast milk and increase the PI in preterm infants, thereby providing additional evidence of the benefit of SSC.

Crystallographic evaluation of the conformation of quetiapine included in ß-cyclodextrin.

Single-crystal X-ray diffraction and theoretical calculations were conducted for insights into the ß-cyclodextrin (ß-CD)-quetiapine inclusion complex structure. ß-CD and quetiapine form a host-guest inclusion complex at a ratio of 2:1 in which the ß-CD molecules form head-to-head dimers with their secondary hydroxyl groups linked by multiple hydrogen bonds. Quetiapine is totally contained within the ß-CD cavity and exhibits two kinds of disorder (parts 1 and 2) in opposite directions in the ß-CD complex. To clarify the mobility of the guest molecule in the ß-CD cavity, theoretical molecular conformational calculations, crystal optimization and crystal energy calculations were conducted using CONFLEX software. The results of theoretical molecular conformation calculations showed that the mobility of quetiapine is restricted because its tricyclic structure is covered by ß-CD. The results of crystal energy calculations indicated that the conformation of disorder part 1, which has high occupancy, was more stable.

Effect of sulfobutyl ether-ß-cyclodextrin and propylene glycol alginate on the solubility of clozapine.

Clozapine (CLZ) is an atypical antipsychotic medication used in the treatment of schizophrenia and is poorly soluble in water (0.05 mM). In this study, we have investigated the effect of ß-cyclodextrin (CD) and its derivatives on the solubility of CLZ. The solubility of the CLZ was measured to generate a phase solubility diagram, and the interaction between CLZ and sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) in aqueous solution was observed by 1H- and 2D rotating-frame Overhauser enhancement spectroscopy (ROESY)-NMR methods. Moreover, the synergistic effect of SBE-ß-CD and water-soluble polymers, including polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium salt, polyvinyl alcohol, sodium alginate, and propylene glycol alginate (PGA), on the solubility of CLZ was investigated. The results show that the solubility of CLZ with 1 w/v% PGA was 7.6 mM, which was almost four times greater than that of CLZ without PGA in a 15 mM SBE-ß-CD solution. In contrast, the solubility of CLZ with 1 w/v % PGA in an aqueous solution decreased by one-third relative to that of CLZ in a 15 mM SBE-ß-CD solution. 2D ROESY-NMR indicated that a CLZ/SBE-ß-CD/PGA ternary complex formed. It was found that the combination of PGA and SBE-ß-CD enhanced the solubility of CLZ.

Crystallographic and theoretical studies of an inclusion complex of ß-cyclodextrin with fentanyl.

The crystal structure of an inclusion complex of ß-cyclodextrin (ß-CD) with fentanyl was determined by single crystal X-ray diffraction analysis. The crystal belongs to the triclinic space group P1 and the complex comprises one fentanyl, two ß-CD, and several water molecules. ß-CD and fentanyl form a host-guest inclusion complex at a ratio of 2:1 and the asymmetric unit of the complex contains two host molecules (ß-CDs) in a head-to-head arrangement that form dimers through hydrogen bonds between the secondary hydroxyl groups of ß-CD and one guest molecule. Fentanyl is totally contained within the ß-CD cavity and the structure of the phenylethyl part of fentanyl inside the dimeric cavity of the complex is disordered. Furthermore, theoretical molecular conformational calculations were conducted to clarify the mobility of the guest molecule in the ß-CD cavity using CONFLEX software. Crystal optimization and crystal energy calculations were also conducted. The results of the theoretical calculations confirmed that the conformation of disorder part 1, which was high in occupancy by crystal structure analysis, was more stable. The phenylethyl part of fentanyl existed in several stable conformations.

Enhanced dissolution and skin permeation profiles of epalrestat with ß-cyclodextrin derivatives using a cogrinding method.

Epalrestat (EPL) is a water-insoluble drug (14µM) that inhibits aldose reductase. This study investigated the interactions between ß-cyclodextrin (CD) derivatives and EPL to determine the solubilizing effect on EPL from phase solubility diagrams. We improved the solubility of EPL in water by adding ß-CD derivatives. Moreover, the solubility of EPL mixed with ß-CD derivatives by cogrinding in a ball mill method was about 2-3 times higher than those of EPL with the same CD concentration (5mM) calculated from phase solubility diagrams. In addition, we investigated the effect of ß-CD derivatives on in vitro percutaneous absorption of EPL through hairless mouse skin. Among the coground mixtures of EPL and ß-CD derivatives, the mixture containing methyl (ME)-ß-CD showed the strongest enhancement of EPL skin permeation. Furthermore, adding 10wt% urea as a skin permeation enhancer after cogrinding with ME-ß-CD improved the flux of EPL 300 times compared to the flux of EPL alone. This result indicates the ME-ß-CD ground mixture system with urea has potential as a new transdermal drug delivery system of EPL for diabetic neuropathy.

Investigation of Discoloration of Furosemide Tablets in a Light-Shielded Environment.

We observed that uncoated furosemide tablets turned yellow in a light-shielded automatic packaging machine and discoloration of the furosemide tablets was heterogeneity and occurred on the surface of the tablets only. The machine was equipped with an internal blower to maintain a constant temperature. Therefore, we investigated the effect of air flow on the discoloration of the furosemide tablets using a blower in a dark environment. The color difference (ΔE) of the furosemide tablets increased linearly as the blowing time increased. We performed structural analysis of the yellow compound in the furosemide tablets by LC-MS and identified the compound as a hydrolysate of furosemide. This suggested that furosemide hydrolysis was accelerated by the air flow. The furosemide tablets were prepared with the most stable furosemide polymorph, form I. X-Ray powder diffractometry and IR spectroscopy showed that during tablet preparation, no crystal transition occurred to an unstable furosemide polymorph. Furthermore, IR spectroscopy showed that the crystal form of furosemide in the yellow portion of the tablets was form I. To elucidate the factors producing the discoloration, we investigated the effect of humidity and atmosphere (air, oxygen, and nitrogen) on the discoloration of the furosemide tablets. The results suggested that the discoloration of the furosemide tablets was accelerated by oxidation, although humidity did not affect the hydrolysis. Therefore, we concluded that the discoloration of the furosemide tablets in the automatic packing machine was caused by acceleration of oxidative degradation by air flow.

Interaction of fentanyl with various cyclodextrins in aqueous solutions.

OBJECTIVES: Water-soluble fentanyl citrate salt has been used in sublingual or buccal formulations for the breakthrough pain treatment. However, fentanyl absorption through the lipid mucosal membrane may be improved by enhancing the non-ionic lipophilic fentanyl base solubility. Therefore, the interaction between cyclodextrins (CDs) and fentanyl base has been evaluated to obtain basic information for its application. METHODS: Parent CDs (α-, ß- and γ-CD) as well as α- and ß-CD derivatives were used for solubility studies with fentanyl base. Nuclear magnetic resonance (NMR) studies were applied in a system including ß-CD or glucosyl-ß-CD (G1-ß-CD) with fentanyl base or fentanyl citrate. (1) H- and (13) C-NMR studies and a two-dimensional rotating frame Overhauser effect spectroscopy (ROESY) study were conducted to confirm inclusion complexes formation. KEY FINDINGS: Parent CDs displayed BS type phase solubility diagrams; ß-CD exhibited a strong interaction with fentanyl base. Hydrophilic ß-CD derivatives, such as G1-ß-CD, displayed AL type phase diagrams and higher solubilizing effects compared with parent CDs. ROESY study suggested that fentanyl phenyl groups were included in ß-CD cavity. CONCLUSIONS: This study revealed that hydrophilic ß-CD derivatives, such as G1-ß-CD, could be useful pharmaceutical additives for oral mucosal formulations because of the improved fentanyl base solubility via inclusion complexation.

Solid-state characterization of sertraline base-ß-cyclodextrin inclusion complex.

Sertraline is one of the serotonin-specific reuptake inhibitors that is effective in treating several disorders such as major depression, obsessive-compulsive disorder, panic disorder, and social phobia. It is marketed in the form of its hydrochloride salt, which exhibits better solubility in water than its free base form. However, the absorption of sertraline through biological membranes could be improved by enhancing the solubility of its base because it is more hydrophobic than sertraline hydrochloride. To clarify the mechanism for the interaction of sertraline base with ß-CD, it is important to study the basic interaction between the ß-CD ring and sertraline base. Therefore, in this study, the currently used hydrochloride salt form was converted into the free base and ß-CD was used as a model for ß-CD derivatives to evaluate the interaction between ß-CD and the sertraline base. The solid-state physicochemical characteristics of the sertraline-ß-CD complex were investigated by the phase solubility method, differential scanning calorimetry, Fourier transform IR spectroscopy, FT-Raman spectroscopy, powder X-ray diffraction, and (13)C cross-polarization magic-angle spinning NMR measurements. The results showed that sertraline base and ß-CD form an inclusion complex, and the stoichiometric ratio of the solid-state sertraline base-ß-CD complex is 1:1, which was estimated by the (1)H NMR measurements of the complex dissolved in DMSO-d6.

Effect of terpenes on the skin permeation of lomerizine dihydrochloride.

PURPOSE: Lomerizine dihydrochloride (LOM) is a Ca2+ channel blocker used as an antimigraine drug, which is currently administered orally in Japan. We therefore investigated the effect of terpenes in propylene glycol (PG) solvent on the percutaneous absorption of LOM by hairless mouse skin. METHODS: Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), confocal laser scanning microscopy (CLSM), and small angle X-ray scattering (SAXS) were carried out to analyze the effects of terpene enhancers on the biophysical properties of the stratum corneum (SC) of the skin. RESULTS: Of the terpenes tested, the highest permeation rate of LOM (28.8 mg/cm2/h) was observed with 1,8-cineole, while nerolidol conferred the lowest enhancement of LOM flux (14.2 mg/cm2/h). ATR-FTIR studies revealed that terpenes/PG induced higher CH2 stretching frequencies of SC lipids than PG alone. The extent of penetration of the lipophilic fluorescence probes Nile Red and DiI was measured by CLSM in in vitro skin permeation studies, using either PG or terpenes/PG as skin permeation enhancers. With PG alone, both fluorescence dyes were undetectable in the skin. In contrast, when co-administered with terpenes/PG, both probes were distributed into the intercellular space between corneocytes and detected in the deeper layers of the skin. SAXS measurements showed that in SC treated with a combination of 1,8-cineole and PG, the scattering peak of the SC was broad and very weak in intensity compared to untreated SC, whereas pretreatment with PG alone did not alter the peak profile. CONCLUSION: A combination of terpenes and PG enhance the skin permeation of LOM. Our findings suggest that the mechanism for this effect involves the ability of terpenes to increase the fluidity of SC lipids, thus enhancing the distribution of LOM into the intercellular region of the SC. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Quetiapine free base complexed with cyclodextrins to improve solubility for parenteral use.

Quetiapine, an antipsychotic drug used for schizophrenia treatment, is poorly water soluble, and therefore, administration of the more water-soluble quetiapine fumarate is preferred. Absorption of quetiapine through biological membranes may be improved by enhancing the solubility of the quetiapine base, the non-ionic form. In this study, the currently used salt form was converted into the free base (oily material). We employed cyclodextrins (CDs) as pharmaceutical additives to improve the solubility of the quetiapine base. The formation of quetiapine-ß-cyclodextrin (ß-CD) complexes was studied by phase solubility studies, continuous variation method, NMR spectroscopy, and powder X-ray diffraction. The formation of a poorly water-soluble complex was confirmed by the phase solubility study, and the interaction between quetiapine and ß-CD in water was confirmed by NMR spectroscopy. In addition, the effects of ß-CD derivatives (glucosyl-ß-CD, maltosyl-ß-CD, 2-hydroxypropyl-ß-CD, dimethyl-ß-CD, and trimethyl-ß-CD) on the solubility of the quetiapine base were studied. The findings indicated that the aforementioned hydrophilic ß-CD derivatives could be used as pharmaceutical additives of quetiapine for parenteral formulations as a result of the improved solubility of the quetiapine base because of inclusion complexation. Therefore, converting the currently used salt form into the free base, investigating the free base as a candidate for CD inclusion, and converting the oily material such as the free base into a powder by forming an inclusion complex that is easy to deal with is considered a worthwhile approach that may lead to novel formulations of the drug in question.

Evaluation of the interaction between ß-cyclodextrin and psychotropic drugs by surface plasmon resonance assay with a Biacore ® system.

Phase-solubility studies have been used to evaluate the solubilizing effects of cyclodextrins (CDs) on lipophilic, water-insoluble drugs. However, large amounts of CDs and drugs are required to measure solubility by phase-solubility studies. Thus, more efficient approaches to evaluate the interaction of CDs with drugs are needed. Herein we introduce a method that evaluates the interaction between immobilized ß-cyclodextrin and psychotropic drugs by surface plasmon resonance assay with a Biacore(®) system. Association constants and stoichiometries observed were generally consistent with values calculated by traditional methods, such as phase-solubility and continuous variation methods. Results showed that the analytical method using Biacore(®) was suitable to evaluate CD-drug interactions.

Effects of cogrinding with ß-cyclodextrin on the solid state fentanyl.

Fentanyl base and ß-cyclodextrin (ß-CD) were coground at 1:1 and 1:2 molar ratios (fentanyl: ß-CD) and the physicochemical characteristics of the mixtures were studied using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), solid state (13)C nuclear magnetic resonance (NMR) spectroscopy and powder X-ray diffraction (PXRD) measurement. Additionally, portions of the coground samples were exposed to high relative humidity to investigate fentanyl and ß-CD interactions. The results of DSC and PXRD analyses indicate that the ground mixtures are in an amorphous state, and the FTIR measurements show hydrogen bonding interactions between fentanyl and ß-CD. Solid state (13)C NMR indicates that a fentanyl/ß-CD inclusion compound is formed in the humidified mixture. Furthermore, PXRD data from the humidified mixtures are similar to the PXRD patterns from the inclusion complex.

Effects of various cyclodextrins on the stability of freeze-dried lactate dehydrogenase.

The effects of eight cyclodextrins (CDs) on the stability of freeze-dried lactate dehydrogenase (LDH) were investigated. Five low-molecular weight saccharides were used as a reference. In the samples without saccharides, LDH activity was decreased by freeze-drying. The LDH activities of the samples with 2-hydroxypropylated CDs (HP-CDs) such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) showed only a small decrease and were more effective protein stabilizers than low-molecular weight saccharides. HP-beta-CD more effectively stabilized LDH than trehalose, at a sugar concentration of less than 1.0 w/w% and furthermore, a close relationship existed between the highly stabilizing effect and the degree of substitution of polar substituents.

Immunochemical detection of 3-deoxyglucosone in serum.

3-Deoxyglucosone (3-DG) is a metabolite of glucose that is thought to lead to the production of advanced glycation end products in diabetes. The previous assay for 3-DG in serum was based on a multi-step protocol, including derivatization, extraction, HPLC separation, and detection. In the current studies, we established a monoclonal antibody that recognizes the 3-DG-derivative, which is generated by the reaction of 3-DG and a 2,3-diamino-benzene derivative. Attachment of a biotin moiety to the 2,3-diamino-benzene ring via a linker allowed development of a highly sensitive chemiluminescent enzyme immunoassay for 3-DG equivalents. Unlike the previous assay, this method does not require extraction of 3-DG derivatives from serum. Treatment of 3-DG in serum with the DAB-link-biotin produced a quinoxaline derivative, which was specifically recognized by the monoclonal antibody. Using this assay, we found that serum 3-DG was higher in streptozotocin-induced diabetic rats than in normal control rats (25+/-5.6 vs. 9.8+/-1.1 microg/L). This simple assay may allow the monitoring of conditions leading to the accumulation of advanced glycation end products and evaluation of the risk of complications in diabetic patients.

Enhancement of water solubility of fullerene by cogrinding with mixture of cycloamyloses, novel cyclic alpha-1,4-glucans, via solid-solid mechanochemical reaction.

Improvement of solubility for fullerene (C60) was studied by cogrinding with cycloamyloses using a ball mill in the solid state. Cycloamylose is a novel cyclic alpha-1,4-glucan produced from synthetic amylose by enzymatic reaction. Although sample solutions showed a pale yellow for the initial period of cogrinding with cycloamyloses and C60, the color varied to brown after 48 h. Subsequently, the solubility of C60 was improved markedly to 560 (microg/ml) at 96 h. From powder X-ray diffraction analysis, the peak intensity of crystalline C60 decreased as the cogrinding time was extended. The UV-VIS absorption spectrum of C60 shows absorption bands at 262 and 340 nm in water with cycloamyloses, and 258 and 328 nm in n-hexane. These results suggested that C60 molecules were dispersed into cycloamyloses micellar system and the red-shift of the UV-VIS spectra was due to an intermolecular interaction between C60 and cycloamyloses.

X-ray structure of the delta-cyclodextrin complex with cycloundecanone.

The crystal structure of the delta-cyclodextrin complex with cycloundecanone shows a channel-type structure consisting of head-to-head dimer units that include four guest molecules.

An anhydrous polymorphic form of trehalose.

An anhydrous polymorphic form of alpha,alpha-trehalose was prepared from trehalose dihydrate by two different drying methods: (1) heating under vacuum; and (2) heating in hot air. Preparation of this anhydrous form by vacuum heating showed good reproducibility. This form was characterized by X-ray powder diffraction analysis and differential scanning calorimetry. This anhydrous form was converted to an amorphous phase at 127 degrees C and was found to be hygroscopic. At 43% relative humidity at 25 degrees C, this form rapidly reverted to dihydrate, while the amorphous phase remained unchanged. When an amorphous phase coexisted with this form, the rate of water adsorption to the amorphous phase was slower than that to the amorphous phase alone. These properties of this anhydrous form of alpha,alpha-trehalose may explain the effects of trehalose in dehydration tolerance of plants and insects in the desert.