Utility of 2-hydroxypropyl-beta-cyclodextrin in an intramuscular injectable preparation of nimodipine

Possible utility of hydroxyalkylated beta-cyclodextrin (beta-CyD) derivatives as parenteral drug carriers was investigated, using nimodipine, a dihydropyridine derivative with calcium antagonistic action, as a model drug. The aqueous solubility of nimodipine increased linearly with increase in the concentration of hydroxyalkylated beta-CyDs, showing an AL-type phase solubility diagram. The stability constant of nimodipine--hydroxyalkylated beta-CyD complexes was in the order of 2,3-dihydroxypropyl-beta-CyD less than beta-CyD less than 2-hydroxyethyl-beta-CyD less than 3-hydroxypropyl-beta-CyD less than 2-hydroxypropyl-beta-CyD, and the solubilizing ability of the beta-CyDs was also in that order. The results of powder X-ray diffractometry and thermal analysis suggested 1:3 (guest:host) complex formation of nimodipine with 2-hydroxypropyl-beta-CyD in the solid state. The dissolution rate of nimodipine-2-hydroxypropyl-beta-CyD complex was much faster than that of the drug alone. Nimodipine-2-hydroxypropyl-beta-CyD complex gave higher plasma levels of the drug after intramuscular administration to rabbits, i.e., the area under the plasma concentration--time curve and the maximum plasma concentration of the complex were about 2.5 times higher than those of the drug alone. The muscular damage after the injection of nimodipine was reduced by the administration of the complexed form.     

Biquinolino-modified beta-cyclodextrin dimers and their metal complexes as efficient fluorescent sensors for the molecular recognition of steroids

A series of bridged beta-cyclodextrin (beta-CyD) dimers possessing functional tethers of various lengths was synthesized in moderate yield by the treatment of 2,2'-biquinoline- 4,4'-dicarboxylic dichloride with beta-CyD or mono[6-oligo(ethylenediamino)-6-deoxy]-beta-CyDs. The products were 2,2'-biquinoline-4,4'-dicarboxy-bridged bis(6-O-beta-CyD) (8), N,N'-bis(2-aminoethyl)-2,2'-biquinoline-4,4'-dicarboxamide-bridged bis(6-amino-6-deoxy-beta-CyD) (9), and N,N'-bis(5-amino-3-azapentyl)-2,2'-biquinoline-4,4'-dicarboxamide-bridged bis(6-amino-6-deoxy-beta-CyD) (10). The reaction of 8-10 with copper perchlorate give their copper(II) complexes 11-13 in satisfactory yields of over 77 %. All the bis(beta-CyD)s 8-13 act as efficient fluorescent sensors and display remarkable fluorescence enhancement upon addition of optically inert steroids. The inclusion complexation behaviors of 8-13 when treated with the representative steroids cholate (14), deoxycholate (15), and glycocholate (16) in aqueous solution at 25 degrees C were investigated by means of UV/Vis spectroscopy, conductivity and fluorescence measurements, circular dichroism spectroscopy, and 2D NMR spectroscopy. The tether length of bis(beta-CyD) 9 allows it to adopt a cooperative host-tether-guest binding mode in which the spacer and guest are co-included in the two CyD cavities. As a result of this cooperation, 9 has a stability constant (K(s)) about 2x10(2) times higher than that of monomodified beta-CyD 4 for inclusion complexation with cholate. Metallooligo(beta-CyD)s with four beta-CyD units have enhanced binding abilities compared with monomodified beta-CyDs. These metallo compounds have binding affinities for guest steroids that are up to 50-4.1x10(3) times higher than those of CyDs 2-4. The guest-induced fluorescence enhancement of bis(CyD)s opens a new channel for the design of sensor materials. The complex stability constants of these compounds are discussed from the viewpoint of induced-fit interaction and cooperative multiple binding between host and guest.     

Structure-antimicrobial activity relationship between pleurocidin and its enantiomer

To develop novel antibiotic peptides useful as therapeutic drugs, the enantiomeric analogue of pleurocidin (Ple), which is a well known 25-mer antimicrobial peptide, was designed for proteolytic resistance by D-amino acids substitution. The proteolytic resistance was confirmed by using HPLC after the digestion with various proteases. To investigate the antibiotic effect of L- and D-Ple, the antibacterial activity and hemolytic effect were tested against human erythrocytes. The D-Ple showed a decreased antibacterial activity and a dramatically decreased hemolytic activity compared with L-Ple. The hemolytic effect of analogue was further confirmed by using calcein leakage measurement with liposome. To elucidate these results, the secondary structure of the peptides was investigated by using circular dichroism spectroscopy. The results revealed that D-Ple, as well as L-Ple, had typical alpha-helical structures which were mirror images, with a different helicity. These results suggested that the discrepancy of the structure between the two peptides made their antibacterial activity distinct.     

Cooperative self-assembly and molecular binding behavior of cyclodextrin-crown ether conjugates mediated by alkali metal ions

In order to quantitatively investigate their molecular binding ability, a series of cyclodextrin-crown ether conjugates containing beta-cyclodextrin (beta-CyD) and crown ether units, i.e.N-(benzoaza-15-crown-5)acylaminomethylene tethered 6-diethylenetriamino-6-deoxy-beta-CyD, N-(benzoaza-15-crown-5)acylaminomethylene tethered 6-triethylenetetraamino-6-deoxy-beta-CyD and 4',5'-dimethylene-benzo-15-crown-5 tethered 6-diethylenetriamino-6-deoxy-beta-CyD, have been prepared as ditopic molecular receptors. Their inclusion complexation behavior with four representative fluorescent dyes, i.e. ammonium 8-anilino-1-naphthalenesulfonate (ANS), sodium 6-toluidino-2-naphthalenesulfonate (TNS), acridine red (AR) and rhodamine B (RhB), has been comprehensively investigated in aqueous NaH2PO4/Na2HPO4 or KH2PO4/K2HPO4 buffer solution (pH 7.20) by means of circular dichroism, fluorescence, and 2D NMR spectra. The results indicate that the self-assembly of crown ether modified beta-CyD mediated by potassium ion exhibits a dimeric structure, which significantly enhances the original binding ability and molecular selectivity of parent beta-CyD and its derivatives towards guest molecules through the cooperative binding of two hydrophobic CyD cavities with one guest. This cooperative binding mode of K+/CyD-crown ether systems are further confirmed by Job's experiments and 2D NMR investigations. Attributed to the positive contributions from the metal-ligated crown ether cap and K+-mediated dimerization of CyDs, the binding constant (Ks) values of CyD-crown ether conjugates toward ANS are 10-83 times higher than that of beta-CyD. The increased binding ability and molecular selectivity of CyD-crown ether conjugates are discussed from the viewpoints of size/shape-fit and multiple recognition mechanism.     

Effects of glycerol and sorbitol on the thermal dependence of the lysis of human erythrocytes by ethanol

In this work, the effects of 1 mol/L glycerol or sorbitol on the thermal dependence (27-47 degrees C) of the lysis of human erythrocytes by ethanol in saline solution (0.154 mol/L NaCl) have been evaluated. Lysis was monitored by measurement of the absorbance at 540 nm. Ethanol produced either lysis or protection against lysis depending on the conditions. These antagonistic effects are attributed to the existence of expanded (R) and compacted (T) erythrocytes, present under conditions of low and high osmolarity, respectively. The transitions of lysis of the R state and formation and lysis of the T state were all found to be sigmoidally defined. The ethanol concentration at the midpoint of the lysis transition of the R state (D(50R)) was found to decrease with increasing temperature and osmolarity. In the presence of glycerol or sorbitol, an increase in temperature led to smaller decreases in D(50R) and osmotic protection against lysis. The ethanol concentration at the midpoint of formation (S(50T)) and lysis (D(50T)) of the T state also decreased with increasing temperature and osmolarity. Lysis of R state erythrocytes is determined by the chaotropic action of ethanol, but the formation and lysis of T state erythrocytes are determined by osmotic pressure effects.     

Two new steroidal saponins, hylodoside A and novaeguinoside Y, from the starfish Leptasterias hylodes reticulata and Culcita novaeguineae (juvenile)

New steroid glycosides, hylodoside A (1) and novaeguinoside Y (2), along with previously known polyhydroxylated steroids (3-7) were isolated from the ethanolic extracts of the starfish Leptasterias hylodes reticulata and Culcita novaeguineae (juvenile). The structures have been elucidated using 1D and 2D NMR spectra (1H, 13C, DEPT, COSY-45, 1D-TOCSY, HSQCGP, ROESY, HSQC and HMBCGP) and mass spectrometry. Compound 3 was shown to inhibit the growth of Staphylococcus aureus up to 10% from the control at a concentration of 1 mg/mL. Steroids 1, 2 and 5 showed moderate hemolytic activity in the mouse erythrocytes assay. Compounds 3, 4 and 6 displayed pH-depended hemolytic properties.     

Multidrug analysis of pharmaceutical and urine matrices by on‐line coupled capillary electrophoresis and triple quadrupole mass spectrometry

The present work illustrates potentialities of CE hyphenated with MS/MS for the simultaneous determination and identification of a mixture of simultaneously acting drugs in pharmaceutical and biological matrices. Here, the hyphenation was provided by ESI interface, while the MS/MS technique was based on the triple quadrupole configuration. Three drugs, namely pheniramine, phenylephrine, and paracetamol were determined and identified with high reliability due to their characterization in three different dimensions, i.e. electrophoresis and MS/MS, that prevented practically any interference. Appropriately selected transitions of the analytes (parent ion‐quantifier product ion‐qualifier product ion) provided their selective determination at maximum S/N. The proposed CE‐MS/MS method was validated (LOD/LOQ, linearity, precision, recovery, accuracy) and applied for (i) the multidrug composition pharmaceuticals, namely Theraflu®, and (ii) human urine taken after per‐oral administration of the same pharmaceutical preparation. The method was applied also for the investigation of potential weak associates of the drugs and monitoring of predicted (bio)degradation products of the drugs. Successful validation and application of the proposed method suggest its routine use in highly effective and reliable advanced drug control and biomedical research.     

Effect of cyclodextrins on biological membrane. I. Effect of cyclodextrins on the absorption of a non-absorbable drug from rat small intestine and rectum

The effects of three kinds of cyclodextrins (CyDs), alpha-, beta- and gamma-CyD on biological membranes were investigated by changes in absorption of a non-absorbable drug, sulfanilic acid (SA), from the rat small intestine and rectum using an in situ perfusion technique. The absorption of SA from the intestine was slight and was not affected by the addition of CyDs. After pretreatment with a mucolytic agent, N-acetyl-L-cysteine (N-Ac), the absorption of SA was increased compared with SA alone in the presence of only beta-CyD. Similar treatment with sodium deoxycholate (SDC) and sodium lauryl sulfate (SLS) to gastro-intestinal membrane showed the enhanced absorption of SA by the addition of beta-CyD. The mucin layer on the surface of the gastro-intestinal membrane may play an important role in the absorption of drugs. On the other hand, enhanced absorption of SA from the rat rectum was not induced by beta-CyD with or without pretreatment with N-Ac, SDC or SLS. Simultaneously, the release of neutral sugars in the perfusate after treatment with adjuvants was also observed with N-Ac, SDC and SLS. These results indicate that the mucin layer works as a barrier to the increased absorption of SA by beta-CyD.     

Rheology of novel self-thickening cationic gemini surfactant solutions

A new cationic Gemini surfactant (25-HP-25) was synthesized with eruamidopropyl dimethylamine and epichlorohydrin, and its solution is self-thickening. The rheological properties of 25-HP-25 and 3-chloro-2-hydroxypropyl eruamidopropyl dimethyl ammonium acetate (EDAA) solutions were compared. The solution of EDAA behaves as Newtonian fluid (1?s^?1??1). Whereas the 25-HP-25 micelle solution (2?wt%) exhibits higher viscosity, which is about three hundred times than that of EDAA solution at low shear rate (γ??1). Especially, the 25-HP-25 solution shows obvious thixotropy, and with the increase of concentration, the viscoelasticity becomes better. Furthermore, the compaction of network structures has been confirmed by cryo-field emission scanning electron microscopy (cryo-FESEM) micrographs. This work is expected to enrich the research field of self-thickening surfactant.     

Microanalyses of beta-cyclodextrin in plasma by high-performance liquid chromatography

Procedures for the micro-determination of beta-cyclodextrin (beta-CyD) in plasma were investigated by four methods using high-performance liquid chromatography (HPLC). In methods A and B, underivatized beta-CyD was detected with a refractive index detector and determined by the absolute calibration graph method. An NH2-bonded silica/acetonitrile-water system was used in A and a C18-bonded silica/methanol-water system in B. In method C, the percarbanilate of beta-CyD was separated on a C8-bonded silica column with acetonitrile-water and determined using gamma-CyD as the internal standard with a UV detector at 231 nm. In method D, the per[1-14C]acetate of beta-CyD was fractionated on a silica column with n-hexane-ethanol containing 1% of water and the radioactivity of each fraction was measured with a liquid scintillation counter. gamma-CyD was used as the internal standard. Interfering plasma proteins were removed by centrifugal ultrafiltration with an MPS-1 micro-partition system. Method B was superior to the other methods with respect to ease of sample preparation, sensitivity and time required for analysis. The cumulative amount of beta-CyD in the mesenteric vein absorbed from the rat intestinal lumen after administration of phenobarbital-beta-CyD complex in a closed loop method was determined by the use of method B.     

Studies on dodecyl betainate in combination with its degradation products or with phosphatidyl choline-phase behavior and hemolytic activity

Surface active betaine esters contain a hydrolysable bond and give naturally occurring products (fatty alcohol and the amino acid betaine) on degradation. They are therefore interesting candidates for use as cationic surfactants in pharmaceutical applications. In this work the phase behavior of two systems of relevance for the utilization of dodecyl betainate as a pharmaceutical excipient is studied, namely dodecyl betainate/dodecanol/betaine hydrochloride/D2O and dodecyl betainate/phosphatidyl choline (PC)/ethanol/D2O. The techniques used for phase characterisation were 2H NMR measured on the solvent, small angle X-ray spectroscopy and optical microscopy. Dilute dodecyl betainate/PC dispersions were characterized using laser diffraction. It is shown that introduction of relatively small amounts of the hydrolysis products of dodecyl betainate, i.e., dodecanol and betaine (used in the form of betaine hydrochloride), has a strong effect on the phase behavior of the binary dodecyl betainate/D2O system. The degradation products change the average curvature of the surfactant film so that, instead of a hexagonal phase at concentrations above the micellar phase, a probably defective, lamellar phase seems to form. The dodecyl betainate/PC/ethanol/D2O system shows a large region of a highly swelling lamellar phase. Dispersions of dodecyl betainate/PC/ethanol in water can be prepared with low energy input; i.e., the preconcentrate can be regarded as a self-dispersing solution. Introduction of dodecyl betainate and its degradation products does not impair the ability of PC to form vesicles. Experiments for evaluating the toxicity of surface active betaine esters to erythrocytes were also performed. There are indications that the hemolytic activity of dodecyl betainate is lower than that of the stable surfactant tetradecyltrimethylammonium chloride, which has similar critical micelle concentration. A combination of dodecyl betainate and PC gives very low hemolytic activity.     

Quantitative determinations of levofloxacin and rifampicin in pharmaceutical and urine samples using nuclear magnetic resonance spectroscopy

Rapid, specific and simple methods for determining levofloxacin and rifampicin antibiotic drugs in pharmaceutical and human urine samples were developed. The methods are based on (1)H NMR spectroscopy using maleic acid as an internal standard and DMSO-d6 as NMR solvent. Integration of NMR signals at 8.9 and 8.2 ppm were, respectively, used for calculating the concentration of levofloxacin and rifampicin drugs per unit dose. Maleic acid signal at 6.2 ppm was used as the reference signal. Recoveries of (97.0-99.4)+/-0.5 and (98.3-99.7)+/-1.08% were obtained for pure levofloxacin and rifampicin, respectively. Corresponding recoveries of 98.5-100.3 and 96.8-100.0 were, respectively, obtained in pharmaceutical capsules and urine samples. Relative standard deviations (R.S.D.) values < or =2.7 were obtained for analyzed drugs in pure, pharmaceutical and urine samples. Statistical Student's t-test gave t-values < or =2.87 indicating insignificant difference between the real and the experimental values at the 95% confidence level. F-test revealed insignificant difference in precisions between the developed NMR methods and each of fluorimetric and HPLC methods for analyzing levofloxacin and rifampicin.     

Hydrolysis behavior of prednisolone 21-hemisuccinate/beta-cyclodextrin amide conjugate: involvement of intramolecular catalysis of amide group in drug release

Prednisolone 21-hemisuccinate/beta-cyclodextrin (beta-CyD) amide conjugate was prepared by binding prednisolone 21-hemisuccinate covalently to the amino group of mono(6-deoxy-6-amino)-beta-CyD through amide linkage. Prednisolone 21-hemisuccinate was intramolecularly transformed to prednisolone 17-hemisuccinate, and the parent drug, prednisolone, was slowly released from the 21-hemisuccinate with a half life of 69 h in pH 7.0 at 37 degrees C; the drug release at 25 degrees C was less than 10% for 48 h. In sharp contrast, the hydrolysis of prednisolone 21-hemisuccinate/beta-CyD amide conjugate was significantly faster (half life of 6.50 min at 25 degrees C) and gave prednisolone and mono(6-deoxy-6-succimino)-beta-CyD as products. The hydrolysis of the beta-CyD amide conjugate was subject to a specific-base catalysis in the alkaline region. The rapid hydrolysis of the conjugate can be ascribed to the involvement of an intramolecular nucleophilic catalysis of the amide group in the reaction. The succinic acid, bound to a drug through ester linkage at one carboxylic group and bound to a pro-moiety through amide linkage at another carboxylic group, may be useful as a spacer for construction of the immediate release type prodrugs of CyDs.     

A tolbutamide–metformin salt based on antidiabetic drug combinations: synthesis,crystal structure analysis and pharmaceutical properties

A drug–drug anhydrous pharmaceutical salt containing tolbutamide {systematic name: 3‐butyl‐1‐[(4‐methylbenzene)sulfonyl]urea, TOL, C₁₂H₁₈N₂O₃S} and metformin (systematic name: 1‐carbamimidamido‐N,N‐dimethylmethanimidamide, MET, C₄H₁₁N₅) was created based on antidiabetic drug combinations to overcome the poor pharmaceutical properties of the parent drugs. Proton transfer and the proportion of the two components were confirmed by ¹H NMR spectroscopy and single‐crystal X‐ray diffraction analysis. Comprehensive characterization of the new pharmaceutical salt crystal, 2‐[(dimethylamino)(iminiumyl)methyl]guanidine (butylcarbamoyl)[(4‐methylbenzene)sulfonyl]azanide, C₄H₁₂N₅⁺·C₁₂H₁₇N₂O₃S^?, was performed and showed enhancement of the pharmaceutical properties, such as lower hygroscopicity and greater accelerated stability than the parent drug MET, and higher solubility and dissolution rate than TOL. The property alterations were correlated with the crystal packing features and potential hydrogen‐bonding sites through observed changes in the crystal structures.     

Analysis of the phase solubility diagram of a phenacetin/competitor/beta-cyclodextrin ternary system, involving competitive inclusion complexation

The competitive inclusion complexations in the ternary phenacetin/competitors/beta-cyclodextrin (beta-CyD) systems were investigated by the solubility method, where m-bromobenzoic acid (m-BBA) and o-toluic acid (o-TA) were used as competitors. The solubility changes of the drug and competitors as a function of beta-CyD concentration in the ternary systems were formulated using their stability constants and intrinsic solubilities. The decrease in solubility of phenacetin by the addition of competitors could be quantitatively simulated by the formulation, when both drug and competitor give A(L) type solubility diagrams. On the other hand, when one of the guests gives a B(S) type solubility diagram, its solubility change was clearly reflected in that of the another guest, i.e., phenacetin gave an A(L) type solubility diagram in the binary phenacetin/beta-CyD system and o-TA gave a B(S) type diagram in the binary o-TA/beta-CyD system, but in the ternary phenacetin/o-TA/beta-CyD system, a new plateau region appeared in the original A(L) type diagram of phenacetin. This was explained by the solubilization theory of Higuchi and Connors. The solubility analysis of the ternary drug/competitor/CyD systems may be particularly useful for determination of the stability constant of a drug whose physicochemical and spectroscopic analyses are difficult, because they can be calculated by monitoring the solubility change of a competitor, without monitoring that of a drug. Furthermore, the present results suggest that attention should be paid to the type of the phase solubility diagram, as well as the magnitude of the stability constant and the solubility of the complex, for a rational formulation design of CyD complexes.     

Photohemolysis sensitized by the furocoumarin imperatorin and its oxyfunctionalized derivatives

The dark and photosensitized (366 nm) hemolytic effects of imperatorin and its photooxidation products, the hydroperoxides I and II as well as the corresponding alcohol of the hydroperoxide I (imperatorin alcohol), were studied on human erythrocytes. Imperatorin was shown to photosensitize hemolysis, its fluence (D) dependence of the rate of photohemolysis (V) followed the equation V = V0 + aD2 + bD1/2, in which V0 is the dark hemolysis rate and a and b are constants. At fluences below 200 kJ/m2, the main hemolytic contribution derives from the bD1/2 component, which is due to the in situ formation of the imperatorin hydroperoxides, while at fluences higher than 200 kJ/m2, the main contribution corresponds to the aD2 component due to the two-photon damage of cell membranes. Hydroperoxides I and II induce oxyhemoglobin cross-linking, as well as its conversion to methemoglobin and hemichrome. These reactions involve hydroxyl and alkoxy radicals, as the hemolysis and oxyhemoglobin conversion could be inhibited by t-butanol and butylated hydrotoluene. For comparison, the dark hemolytic effect of the imperatorin alcohol was approximately 10-fold less than of the hydroperoxides.     

Improvement of dissolution properties of a new Helicobacter pylori eradicating agent (TG44) by inclusion complexation with beta-cyclodextrin

The interaction of a newly developed Helicobacter pylori eradicating agent (TG44, 4-methylbenzyl-4'-[trans-4-(guanidinomethyl)cyclohexylcarbonyloxy]biphenyl-4-carboxlylate monohydrochloride) with beta-cyclodextrin (beta-CyD) in aqueous solution and in solid state was studied to gain insight into the high in-vivo H. pylori eradicating activity of TG44/beta-CyD complex. The interaction was studied by the solubility method, spectroscopic methods, powder X-ray diffractometry and differential scanning colorimetry (DSC). TG44 gave A(L)-type phase solubility diagram with beta-CyD in water, showing a linear increase in solubility of the drug up to 8 mM beta-CyD concentration. The solubility of TG44 (0.04 mM in water at 25 degrees C) increased about 70-folds at 8 mM beta-CyD. Ultraviolet, circular dichroism, fluorescence and (1)H-nuclear magnetic resonance spectroscopic studies indicated that TG44 forms the inclusion complex with beta-CyD in a 1:1 stoichiometry and the biphenyl moiety of TG44 is preferably included in the beta-CyD cavity in water. The Giordano plot made by monitoring changes in the fusion enthalpy of TG44 (about 184 degrees C) suggested that TG44 forms the 1:1 complex with beta-CyD in the solid state. The TG44/beta-CyD solid complex in a 1:1 stoichiometry was prepared by the grinding and spray-drying methods and confirmed by powder X-ray diffractometry and DSC that the complex is in an amorphous state. The initial dissolution rate of TG44/beta-CyD complex was significantly faster than those of the drug alone and the physical mixture of both components, maintaining higher supersaturated concentrations of the drug for a long time. The results suggested that the higher eradicating activity of TG44/beta-CyD complex to Helicobacter pylori, compared with that of the drug alone, is attributable at least partly to the faster dissolving property of the complex and its ability to maintain the supersaturated state of the drug in the gastric fluid.     

Effect of cyclodextrins on biological membrane. II. Mechanism of enhancement on the intestinal absorption of non-absorbable drug by cyclodextrins.

The effects of two kinds of cyclodextrins (CyDs), alpha- and beta-CyD, on biological membranes were investigated by measuring changes in the absorption of a non-absorbable drug, sulfanilic acid (SA), from the rat small intestine, using in situ and in vitro experiments. After pretreatment with a mucolytic agent, N-acetyl-L-cysteine (N-Ac), only beta-CyD increased the absorption of SA significantly compared to the absorption without pretreatment. The mechanism of the enhancing effect of CyDs on the absorption of SA was discussed. Almost no morphological change in the small intestine was observed by pretreatment with N-Ac alone, N-Ac or alpha- or beta-CyD combinations. The liberation of membrane components differed among the CyDs, e.g., alpha-CyD selectively released phospholipid while beta-CyD released mainly cholesterol from the intestinal membrane. It is suggested that the interaction of membrane components with CyDs may be at least partly responsible for the enhanced absorption of SA. Moreover it was found from in vitro electrophysiological experiment, that the alteration in enhanced permeability caused by beta-CyD occurred primarily in the transcellular pathways, rather than in the paracellular pathways of the small intestine. These results suggest that the enhancement of intestinal absorption by beta-CyD, after removal of the mucin layer from the intestinal surface, is due to the interaction between the membrane components and CyD. This interaction would induce disorder in cell membrane lipid, resulting in the increased permeability of the transcellular route.     

Inclusion effect and structural basis of cyclodextrins for increased extraction of medicinal alkaloids from natural medicines

The enhancing effects of alpha-, beta-, and gamma-cyclodextrins (CyDs) on the aqueous extraction of ephedrine and berberine from the natural medicines were investigated in HPLC analysis, and the greatest effect was observed for beta- and gamma-CyDs. To clarify the structural basis of such an increased extraction effect with beta-CyD, possible interaction modes of (1R,2S)-ephedrine with alpha-, beta-, and gamma-CyDs were investigated using molecular dynamic simulations in an aqueous solution system. It was shown that the wrapping model of ephedrine by beta-CyD is the most compact and thus increases the solubility most effectively, compared with those by other CyDs. The same mode could be possible for the greatest effect of gamma-CyD on the extraction of berberine from natural medicines. This clearly shows that CyDs are useful additives for the effective extraction of bioactive alkaloids from natural medicines.     

Studies on Pyrazine Derivatives. 39. Synthesis,Reactions, and Tuberculostatic Activity of 3-Pyrazinyl-1,2,4-triazolo[4,3-<Emphasis Type="Italic">a</Emphasis>]-1,3-diazacycloalkanes

In the reactions of S,S-dimethyldithiocarbamate pyrazinoylhydrazone with diamines some 3-pyrazinyl-1,2,4-triazolo[4,3-a]-1,3-diazacycloalkanes were obtained, and the mechanism of their formation was proposed. The products were acylated, hydroxyalkylated, and aminomethylated. Their tuberculostatic activity was tested in vitro.__________Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 230–237, February, 2005.