Showing papers in "Chemical & Pharmaceutical Bulletin in 2009"

Identification of a cannabinoid analog as a new type of designer drug in a herbal product.

Abstract: A new type of designer drug, a cannabinoid analog (1), was found in a herbal product distributed on the illegal drug market in Japan in expectation of its narcotic effect. The structure of 1 was identified by LC-MS, GC-MS, high-resolution MS, and NMR analyses. Compound 1 showed a molecular weight of 332, and accurate mass measurement exhibited its elemental composition to be C(22)H(36)O(2). Together, the mass and NMR spectrometric data revealed that 1 was (1RS,3SR)-3-[4-(1,1-dimethyloctyl)-2-hydroxyphenyl]cyclohexan-1-ol, which was first synthesized in 1979 by a group at Pfizer Inc. and reported as a potent cannabinoid analog possessing cannabinoid receptor binding activity and analgesic activity in the 1990 s. This is the first report to identify a cannabinoid analog in an illegal drug.

Naturally occurring iridoids, secoiridoids and their bioactivity. An updated review, Part 3.

Abstract: Naturally occurring new iridoids and secoiridoids published during 2005-2008 are reviewed with available physical and spectral data: mp, [alpha](D), UV, IR, (1)H- and (13)C-NMR and plant source. The works on biological and pharmacological activity of naturally occurring iridoids and secoiridoids reported during 2005-2008 are also reviewed. Bioactivities like antibacterial, anticancer, anticoagulant, antifungal, anti-inflammatory, antioxidative, antiprotozoal, hepatoprotective and neuroprotective activities are highlighted.

Anti-human immunodeficiency virus-1 protease activity of new lanostane-type triterpenoids from Ganoderma sinense.

Abstract: Five new highly oxygenated lanostane-type triterpenoids [ganoderic acid GS-1 (1), ganoderic acid GS-2 (2), ganoderic acid GS-3 (3), 20(21)-dehydrolucidenic acid N (4) and 20-hydroxylucidenic acid A (5)] were isolated from the fruiting body of Ganoderma sinense, together with known compounds including 6 triterpenoids and 3 sterols. The structures of the new triterpenoids determined by spectroscopic means including 2D NMR were 7beta-hydroxy-3,11,15-trioxo-lanosta-8,24(E)-dien-26-oic acid (1), 7beta,15alpha-dihydroxy-3,11-dioxo-lanosta-8,24(E)-dien-26-oic acid (2), 12beta-acetoxy-3beta,7beta-dihydroxy-11,15-dioxo-lanosta-8,24(E)-dien-26-oic acid (3), 3beta,7beta-dihydroxy-11,15-dioxo-25,26,27-trinorlanosta-8,20-dien-24-oic acid (4), and 7beta,20xi-dihydroxy-3,11,15-trioxo-25,26,27-trinorlanost-8-en-24-oic acid (5), respectively. Among these, ganoderic acid GS-2, 20-hydroxylucidenic acid N, 20(21)-dehydrolucidenic acid N and ganoderiol F inhibited human immunodeficiency virus-1 protease with IC(50) values of 20-40 microM.

Bioactive Flavonoids of the Flowers of Butea monosperma

Abstract: One new dihydrochalcone, dihydromonospermoside (7), was isolated from the flowers of Butea monosperma together with three known chalcones, butein (2), monospermoside (4) and isoliquiritigenin (8), one flavone, 7,3',4'-trihydroxyflavone (6), four flavanones, (-)-butin (1a), (-)-butrin (3a), (+)-isomonospermoside (5b) and (-)-liquiritigenin (9a), and three isoflavones, formononetin (10), afrormosin (11) and formononetin-7-O-beta-D-glucopyranoside (12). The structure of the new compound was elucidated by spectroscopic techniques whereas those of the known compounds were identified by comparisons of spectroscopic and some physical data with those of reported compounds. The absolute configurations at the 2-position of the flavanones 1a, 3a, 5b and 9a were established to be 2S, 2S, 2R and 2S, respectively, by circular dichroism spectral measurements and were confirmed by comparison of the optical rotations with those of reported values and by enzymic hydrolysis of the glucosides to the corresponding aglycones. The isolated flavonoids exhibited varying antimycobacterial activity with the chalcone 2 being the most active compound (MIC 12.5 microg/ml).

Flavonoid and a rare benzophenone glycoside from the leaves of Aquilaria sinensis.

Abstract: From the leaves of Aquilaria sinensis (LOUR) GILG, a novel benzophenone glucoside, designated as aquilarinoside A (1), and a new flavonoid, as 7-beta-D-glucoside of 5-O-methylapigenin (2), along with eight known compounds (3-10) were isolated The structures of 1 and 2 were fully characterized by spectroscopic methods (1D, 2D NMR and MS) and the relative stereochemistry was assigned based on nuclear Overhauser effect spectroscopy (NOESY) correlations and analyses of coupling constants The new compounds showed inhibition activity against polymorphonuclear neutrophils (PMNs) respiratory burst stimulated by PMA

Heptacoordinate tin(IV) compounds derived from pyridine Schiff bases: synthesis, characterization, in vitro cytotoxicity, anti-inflammatory and antioxidant activity.

Abstract: Tin(IV) complexes 2a—q derived from pyridine Schiff bases were prepared and characterized. Four complexes of this series were evaluated in vitro against different carcinogenic cell lines; besides their anti-inflammatory and antioxidant properties were also tested. Combination of mass spectrometry, multinuclear NMR and X-ray diffraction techniques evidenced the formation of heptacoordinated monomeric species. The X-ray diffraction analysis of 2a, 2b, 2i, 2j and 2n led to establish the heptacoordination around the tin atom in solid state and also revealed that the ligand occupies the equatorial positions of the distorted pentagonal bipyramidal geometry and the two alkyl or aryl groups the axial positions. The in-vitro study for complexes 2a—d against six tumor cell lines showed varied antiproliferative activity, the IC50 for all tested complexes was lower than that of the cis-platin. Compounds 2a—d also exhibited anti-inflammatory activity where complex 2c resulted to be more active (IC50=0.11 μM) than the indomethacin IC50=0.27 μM which was used as reference. The antioxidant activity in rat brain homogenate on inhibition of thiobarbituric acid reactive substances (TBARS) indicated that 2c (IC50=1.77 μM) is more active than the quercetine (4.11 μM) and α-tocopherol (IC50=569.09 μM).

Contribution of each amino acid residue in polymyxin B(3) to antimicrobial and lipopolysaccharide binding activity.

Abstract: This study on the structure-activity relationship of polymyxin B, a cyclic peptide antibiotic, used sixteen synthetic polymyxin B(3) analogs including alanine scanning analogs to elucidate the contribution of the side chains to antimicrobial activity and lipopolysaccharide (LPS) binding. Of these analogs, [Ala(5)]-polymyxin B(3) showed greatly reduced antimicrobial activity against Escherichia coli (E. coli), Salmonella Typhimurium (S. Typhimurium) and Pseudomonas aeruginosa (P. aeruginosa) with MIC values of 4-16 nmol/ml, suggesting that the Dab (alpha,gamma-diaminobutyric acid) residue at position 5 is the most important residue contributing to bactericidal activity. The antibacterial contribution of Dab when located within the lactam ring (positions 5, 8 and 9) was greater than when located outside the ring (positions 1 and 3). [D-Ala(6)]-, [L-Phe(6)]-, [Ala(7)]-, and [Gly(7)]-polymyxin B(3) analogs retained potent antimicrobial activity, indicating that neither the reduction of hydrophobic character of the D-Phe(6)-Leu(7) region nor the D-configuration at position 6 is indispensable for antimicrobial activity. LPS binding studies showed that decreased hydrophobicity of the lactam ring had little effect, but the N(gamma)-amino function of the Dab residues at position 1, 3, 5, 8 and 9 greatly affected LPS binding, with the contribution of Dab(5) being the most significant.

Four new bibenzyl derivatives from Dendrobium candidum.

Abstract: Four new bibenzyl derivatives, namely, dendrocandins F-I (1-4), were isolated from the stems of Dendrobium candidum. Their structures were elucidated by the analysis of spectroscopic data. Dendrocandins F and G represent the fourth and fifth example of bisbibenzyl derivates with a dibenzopyran ring between two units, respectively. Dendrocandin H represents the first example of a bibenzyl derivative formed by a bibenzyl and a 1,4-phenanthraquinone unit via a dibenzopyran ring. Compounds 1-4 were examined for antioxidant activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay.

Flavan-3-ols Having a γ-Lactam from the Roots of Actinidia arguta Inhibit the Formation of Advanced Glycation End Products in Vitro

Abstract: Two new flavan-3-ols, 6-(2-pyrrolidinone-5-yl)-(-)-epicatechin (1) and 8-(2-pyrrolidinone-5-yl)-(-)-epicatechin (2), as well as five known compounds, (-)-epicatechin (3), (+)-catechin (4), proanthocyanidin B-4 (5), (+)-pinoresinol, and p-hydroxybenzoic acid, were isolated from an EtOAc-soluble extract of the roots of Actinidia arguta. The structures of compounds 1 and 2 were elucidated by spectroscopic data interpretation, particularly by extensive 1D- and 2D-NMR studies. All the isolates were evaluated in vitro for inhibitory activity on the formation of advanced glycation end products (AGEs). Of these, compounds 1-5 exhibited significant inhibitory activity against AGEs formation with IC50 values ranging from 10.1 to 125.2 mu m.

Gellan Gum Based Microparticles of Metoclopromide Hydrochloride for Intranasal Delivery: Development and Evaluation

Abstract: The purpose of this study was to develop nasal microparticles of metoclopromide employing gellan gum as a polymer by spray drying method. This method of microencapsulation is particularly less dependent on the solubility characteristics of the drug and polymer and is simple, reproducible, and easy to scale up. The microparticles were evaluated for characteristics like particle size, incorporation efficiency, swelling ability, zeta potential, mucoadhesion, thermal analysis, X-ray diffraction (XRD) study and in vitro drug release. The microparticles so prepared had irregular shape and smooth but distorted surface morphology. They were negatively charged. The particle size ranged from 9.38 to 10.67 microm. Differential scanning calorimetry (DSC) studies revealed that metoclopromide was molecularly dispersed inside the microparticles. The swelling was increased with increase in amount of polymer. The release of drug from microparticles was moderately sustained without lag time and attributed to formation of hydrogel; ionically cross linked hydrogel was hypothesized. The formulation was found to be non toxic to nasal tissue. These in vitro preliminary results show that spray dried microparticles based on gellan gum could be suitable nasal delivery system for the administration of metoclopromide.

Physicochemical characterization and drug release of thermosensitive hydrogels composed of a hyaluronic acid/pluronic f127 graft.

Abstract: Pluronic F127 (PF127) is a copolymer which forms thermosensitive hydrogels. Hyaluronic acid (HA) was grafted to PF127 to form a new hydrogel matrix (HP) for delivery of cisplatin and carboplatin. The physicochemical properties and drug delivery of the graft were examined in this study. HP system (20% HP copolymer in water) exhibited a similar sol-gel transition temperature (28.3 degrees C) as PF127 system (20% PF127 copolymer in water) but with a shorter gelling process. A stronger structure was obtained by HP system according to scanning electron microscopic (SEM) images and viscosity kinetics. In vitro release test showed the sustained-release characteristics of hydrogels entrapped with cisplatin and carboplatin. The drug release rate from HP hydrogel was slower than that from PF127 hydrogel. The reduction of drug release by HP system as compared to the control solution was more significant for cisplatin than for carboplatin. Such a thermosensitive hydrogel may be advantageous as an injectable therapeutic formulation for anticancer treatment.

Ginsenosides from Heat Processed Ginseng

Abstract: A new dammarane-glycoside, ginsenoside Rz1 (1), was isolated from heat-treated Panax ginseng C. A. MEYER (Araliaceae) with ginsenosides Rk1 and Rg5. The structure of 1 was established to be (Z)-12β-hydroxydammara-20(22),24-dien-3β-yl O-β-D-glucopyranosyl-(1→2)-β-D-glucospyranoside by spectroscopic means. HPLC analyses revealed that the ginsenosides Rz1, Rk1, and Rg5 were present in the ratios of 1 : 2 : 6, respectively.

Effects of Formulation Parameters on Encapsulation Efficiency and Release Behavior of Risperidone Poly( D , L -lactide-co-glycolide) Microsphere

Abstract: A 4-week sustained release risperidone biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microsphere for the therapy of schizophrenia, the effects of formulation parameters on encapsulation efficiency and release behavior were studied. The risperidone PLGA microspheres were prepared by O/W solvent evaporation method and characterized by HPLC, SEM, laser particle size analysis, GC and HPLC-MS. The results indicated that the morphology of the risperidone PLGA microspheres presented a spherical shape with smooth surface, the particle size was distributed from 32 to 92 μm and the drug encapsulation efficiency was influenced by homogeneous rotation speed, intrinsic viscosity, carboxylic terminal group, the polymer concentration in the oil phase and the molecular weight of the polymer. These changes were also reflected in drug release. When the Mw of the polymers increased from ca. 28000 to ca. 90000, the initial burst release of risperidone PLGA microspheres decreased from 13 to 0.8% and the sustained-release could be extended to 4 weeks. Pharmacokinetic study on beagle dogs showed that the 4-week sustained release profile of the risperidone loaded microspheres prepared with 75253A was verified. The PLGA 75253A and 75255A show the potential as excipients for the monthly sustained release risperidone PLGA microspheres due to higher encapsulation efficiency and almost zero-order release kinetics of release profile.

Preparation and evaluation of gastroretentive floating tablets of Silymarin.

Abstract: The present study performed by preparation and evaluation of floating tablets of Silymarin as model drug for prolongation of gastric residence time. Floating effervescent tablets were formulated by various materials like hydroxypropyl methylcellulose (HPMC) K 4M, K 15M, psyllium husk, swelling agent as crospovidone and microcrystalline cellulose and gas generating agent like sodium bicarbonate and citric acid and evaluated for floating properties, swelling characteristics and in vitro drug release studies. Floating noneffervescent tablets were prepared by polypropylene foam powder and different matrix forming polymers like HPMC K 4M, Carbopol 934P, xanthan gum and sodium alginate. In vitro drug release studies were performed and drug release kinetics evaluated using the linear regression method was found to follow both the Higuchi and the Korsemeyer and Peppas equation. The drug release mechanism was found fickian type in most of the formulations. The developed floating tablets of Silymarin may be used in clinic for prolonged drug release for at least 24 h, thereby improving the bioavailability and patient compliance.

Synthesis of new 2-thio-[1,2,4]triazolo[1,5-c]quinazoline derivatives and its antimicrobial activity.

Abstract: A series of novel ([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)carboxylic acids 2a―d and esters 3a―1 were synthesized and evaluated for antimicrobial activity. Alkylation of potassium 2-thio-[1,2,4]triazolo[1,5-c]quinazoline 1 with halogenocarboxylic acids and its esters proceeded S-regioselectively. During acid catalyzed esterification of 2a―c, degradation of the pyrimidine ring was observed. The structures of the compounds were elucidated by FT-IR, 1 H- and 13 C-NMR, electron impact mass spectra (EI-MS) and LC-MS spectral data. Antimicrobial and antifungal activity of synthesized compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger, Mycobacterium luteum, Candida albicans and Candida tenuis. Acids 2a and 2c exhibited significant activity against C. albicans, which was additionally confirmed by the bioluminescence inhibition test and interrelated with their lipophilicity.

The constituents and their bioactivities of Houttuynia cordata

Abstract: Chemical investigation on the whole plant of Houttuynia cordata has resulted in the isolation of two new compounds, named as houttuynoside A (1) and houttuynamide A (2), together with thirty-eight known compounds. The structures of 1 and 2 were elucidated on the basis of spectroscopic analysis. In the inhibitory effects on herpes simplex virus type 1 (HSV-1) assay, norcepharadione B (10) showed good inhibitory activity against the replication of HSV-1. In addition, the antioxidant and antityrosinase activities of some isolated compounds were also evaluated. Among these compounds, quercitrin (25) and quercetin-3-O-beta-D-galactopyranoside (26) showed excellent 2,2-diphenyl-1-picrylhydrazyl radical-scavenging property with IC50 values of 31 and 63 microM, respectively. Cepharadione B (9) exhibited strong tyrosinase inhibitory activity with an IC50 value of 170 microM.

Synthesis of various kinds of isoflavones, isoflavanes, and biphenyl-ketones and their 1,1-diphenyl-2-picrylhydrazyl radical-scavenging activities.

Abstract: Forty-eight kinds of isoflavones (8), thirty-one isoflavanes (9), and forty-seven biphenyl-ketones (10, 10') were synthesized from eleven kinds of substituted phenols (11) and six phenylacetic acids (12). Among them, seventy-five compounds are new. The radical scavenging activities of these compounds were evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) at pH 6.0. We found that thirty-nine out of forty-three compounds having a catechol moiety on either the A- or the B-ring exhibited a high activity (ED(50)=12-54 microM) similar to that of catechin. In these cases, the remaining part of their structure seemed to have little effect on their activity. Many 6- or 8-hydroxyisoflavanes (9E-I) and their biphenyl-ketone derivatives (10E-H) also showed a high activity (ED(50)=or<50 microM), while all of their corresponding isoflavones (8E-I) were not active at all. The 7-hydroxyisoflavanes having either an additional hydroxyl group at the C5-position (9D) or a methoxy group at the C6-position (9J) presented a high activity (ED(50)=26-32 microM). This study suggests that natural isoflavones have the possibilities of exhibiting antioxidant activities through the hydroxylation at the C6-, C8-, or C3'-position or the formation of the isoflavanes (9) and/or the biphenyl-ketone derivatives (10') by metabolism or biotransformation.

Analysis of binding interaction between bovine serum albumin and the cobalt(II) complex with salicylaldehyde-2-phenylquinoline-4-carboylhydrazone.

Abstract: The interaction between bovine serum albumin (BSA) and the cobalt(II) complex with salicylaldehyde-2-phenylquinoline-4-carboylhydrazone (Co-SPC) was investigated using fluorescence spectroscopy, UV absorption, and circular dichroism (CD) under simulated physiologic conditions for the first time. Fluorescence data and UV absorption spectra revealed that the intrinsic fluorescence of BSA was strongly quenched by Co-SPC in terms of a static quenching process at a lower concentration of the complex and a combined quenching process at a higher concentration of the complex. Binding constants and binding sites were evaluated. The average binding distance between Co-SPC and BSA was obtained (2.28 nm) on the basis of Forster's theory. The thermodynamic parameters indicated that hydrophobic force played a major role in the binding. The binding of Co-SPC to BSA leads to changes in the conformation of BSA according to synchronous fluorescence spectra and CD data.

Explorative study on isoform-selective histone deacetylase inhibitors.

Abstract: Histone deacetylases (HDACs) catalyze the deacetylation of the acetylated lysine residues of histones and non-histone proteins, and are involved in various fundamental life phenomena, such as gene expression and cell cycle progression. Thus far, eighteen HDAC family members (HDAC1-11 and SIRT1-7) have been identified, but the functions of the HDAC isoforms are not yet fully understood. In addition, some of the HDAC isoforms have been suggested to be associated with various disease states, including cancer and neurodegenerative disorders. Therefore, isoform-selective HDAC inhibitors are of great interest, not only as tools for probing the biological functions of the isoforms, but also as candidate therapeutic agents with few side effects. It was against this background that we initiated research programs to identify isoform-selective HDAC inhibitors. We designed HDAC inhibitors based on the three-dimensional structure of the enzyme and on the proposed catalytic mechanism of HDACs, and found several isoform-selective HDAC inhibitors. Furthermore, we elucidated the functions of HDAC6 by chemical genetic approaches using these inhibitors. The results of this research also suggested the feasibility of using isoform-selective HDAC inhibitors as therapeutic agents.

Design and evaluation of polymeric ocular drug delivery system.

Abstract: The objective of the present study was to prepare ocular inserts of Gatifloxacin. The inserts were fabricated by solvent casting technique, with an aim by achieving once a day administration in the treatment of conjunctivitis. Inserts were evaluated for film thickness, weight variation, drug content, percentage moisture absorption and loss. In-vitro drug release studies were done using bi-chambered donar receiver compartment model. The optimized formulations were subjected to in-vivo studies using rabbits as an animal model and stability studies to assess the effectiveness of the formulations. Finally in-vitro and in-vivo correlation was established. In-vitro drug release data was treated according to zero, first, Korsemeyer Peppas and Higuchi kinetics to access the mechanism of drug release. Formulations were found to be uniform in physicochemical parameter with a fewer variations. Plasticizer was found to influence in mechanical properties as well as modify the drug release rate of the films. Prepared ocular inserts exhibited desired release within 24 h and found to be strongly revealing the efficacy of in vitro-in vivo correlation. From stability studies inserts were remained stable both physically and chemically. No burst effect but a prolonged drug release was observed from all formulations. Thus it achieves target such as increased residence time, prolonged drug release, reduction in frequency of administration and may improve the patient compliance.

Interaction of polyphenols with proteins: binding of (-)-epigallocatechin gallate to serum albumin, estimated by induced circular dichroism.

Abstract: The binding of (-)-epigallocatechin gallate (EGCG), a representative natural polyphenol, to human serum albumin (HSA) and bovine serum albumin (BSA) was investigated using induced circular dichroism (CD). The site of the binding EGCG-HSA was analyzed based on the competition with drugs with known binding sites on HSA, such as phenylbutazone (PB) and diazepam (DP). Double-reciprocal plot analyses showed the competitive relations with the site-I- (PB and tolbutamide, TB) and site-II-binding drugs (DP and ibuprofen, IP) indicating the binding of EGCG to sites I and II on HSA, while digitoxin (DG), a site-III-binding drug, did not affect the binding of EGCG. In an analogous way, the competitive relations were observed between EGCG and the site-I- (PB and TB) and site-II-binding (ethacrynic acid, EA) drugs for the binding of EGCG and BSA. The site-III drug DG also showed competitive binding with EGCG to BSA. The binding of EGCG to the albumins indicated its affinity to sites I and II on HSA, while competitive binding for all three sites was observed on BSA.

Nanoparticulation of Poorly Water Soluble Drugs Using a Wet-Mill Process and Physicochemical Properties of the Nanopowders

Abstract: In order to improve the dissolution and oral absorption properties of poorly water soluble drugs such as omeprazole, albendazole and danazol, various dispersing agents were added to prepare nanopowder formulations using an ULTRA APEX MILL, which is a wet-mill instrument, and their physicochemical properties were evaluated. Using Pluronic F-108 or F-68 as dispersing agents, slurries containing drug particles having nanometer size were obtained for all model drugs tested. Omeprazole, a heat labile drug, was not degraded by wet-milling and the omeprazole nanoparticles in a milled slurry did not aggregate for 24 h after wet-milling. After lyophilization of these milled slurries containing drug nanoparticles, fine solid white nanopowders were obtained. Scanning electron microscopy (SEM) suggested that the model drugs were milled into nanometer size. X-ray powder diffraction (XRPD) patterns and Differential Scanning Calorimetry (DSC) curves confirmed that all milled drug nanopowders were crystalline, although milling of albendazole nanopowder transformed it to another crystal form. Wet-milling using an ULTRA APEX MILL offers a highly effective approach to produce stable drug nanopowders and is a very useful tool for bioavailability enhancement of poorly water soluble and heat labile drugs.

Famotidine orally disintegrating tablets: bitterness comparison of original and generic products.

Abstract: The purpose of the present study was to compare the palatability of the original and eight generic versions of famotidine orally disintegrating tablets by means of human gustatory sensation tests, a comparison of the release profiles, and using an automated taste sensor, the alpha-Astree Electronic Tongue. In the gustatory sensation test, the original product (Gaster D, 10 mg) showed the lowest bitterness intensity. Among the eight generic products tested, the variance in the sweetness intensity was not great, but there were large variances in the intensity of bitterness, some of the generic products being significantly more bitter than that of the original product. On the other hand, some generic products show similar bitterness level as the original product. In a study of release profiles, the original product had the lowest release rates of both famotidine and aspartame; in comparison, some of the generic products had high release rates of famotidine and aspartame, even in the initial stages. Whereas some generic products had low release rates of famotidine and aspartame. Finally, sample solutions were analysed using the taste sensor. There was a good correlation between the taste predicted by principal component analysis and the Euclidean distance obtained by the taste sensor, and bitterness intensities obtained in the human gustatory tests.

Absolute stereostructures of olibanumols A, B, C, H, I, and J from olibanum, gum-resin of Boswellia carterii, and inhibitors of nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages.

Abstract: Three new monoterpenes, olibanumols A (1), B (2), and C (3), and three new triterpenes, olibanumols H (4), I (5), and J (6), were isolated from olibanum, the exuded gum-resin from Boswellia carterii BIRDW. Their structures including the absolute configuration were determined by chemical and physicochemical evidence. Among the constituents, olibanumols A (1), H (4), and I (5), and isofouquierol (12) exhibited nitric oxide production inhibitory activity in lipopolysaccharide-activated mouse peritoneal macrophages.

Particle characterization of poorly water-soluble drugs using a spray freeze drying technique.

Abstract: A spray freeze drying (SFD) method was developed to prepare the composite particles of poorly water-soluble drug. The aqueous solution dissolved drug and the functional polymer was sprayed directly into liquid nitrogen. Then, the iced droplets were lyophilized with freeze-dryer to prepare solid particles. Tolbutamide (TBM) and hydroxypropylmethylcellulose (HPMC) were used as a model drug and water-soluble polymeric carrier in this study, respectively. The morphological observation of particles revealed that the spherical particles having porous structure could be obtained by optimizing the loading amount of drug and polymer in the spray solution. Especially, SFD method was characterized that the prepared particles had significantly larger specific surface area comparing with those prepared by the standard spray drying technique. The physicochemical properties of the resultant particles were found to be dependent on the concentration of spray solution. When the solution with high content of drug and polymer was used, the particle size of the resulting composite particles increased and they became spherical. The specific surface area of the particles also increased as a result of higher concentration of solution. The evaluation of spray solution indicated that these results were dependent on the viscosity of spray solution. In addition, when composite particles of TBM were prepared using the SFD method with HPMC as a carrier, the crystallinity of TBM decreased as the proportion of HPMC increased. When the TBM : HPMC ratio reached 1 : 5, the crystallinity of the particles completely disappeared. The dissolution tests showed that the release profiles of poorly water-soluble TBM from SFD composite particles were drastically improved compared to bulk TBM. The 70% release time T(70) of composite particles prepared by the SFD method in a solution of pH 1.2 was quite smaller than that of bulk TBM, while in a solution of pH 6.8, it was slightly lower. In addition, the release rates were faster than those of standard spray dried (SD) composite particles for solutions of pH 1.2 and 6.8, respectively. When composite particles were prepared from mixtures with various composition ratios, T(70) was found to decrease as the proportion of HPMC increased; the release rate was faster than that of bulk TBM in a solution of pH 6.8, as well as solution of pH 1.2.

Brazilian natural medicines. III. structures of triterpene oligoglycosides and lipase inhibitors from mate, leaves of ilex paraguariensis.

Abstract: The methanolic extract from the leaves of Ilex paraguariensis (Aquifoliaceae) was found to show an inhibitory activity on porcine pancreatic lipase. From the methanolic extract, three new triterpene oligoglycosides, mateglycosides A, B, and C, were isolated together with 18 known compounds. The chemical structures of new oligoglycosides were elucidated on the basis of chemical and physicochemical evidence. Several constituents showed inhibitory activities on pancreatic lipase.

Fabrication and Evaluation of Taste Masked Resinate of Risperidone and Its Orally Disintegrating Tablets

Abstract: The present investigation was undertaken to design a simple, rapid, cost effective and highly efficient process to fabricate a tasteless complex of risperidone using ion exchange resin (IER), evaluate the molecular properties of the resinate and finally incorporate it into orally disintegrating tablets (ODT). The resinate formation using Amberlite IRP64, was confirmed using the characterization methods: Fourier transform-infrared (FT-IR), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The maximum loading efficiency achieved was 99.72+/-0.16% in 1 : 4 (drug : resin weight) ratio at pH 6.0, temperature at 22 degrees C in a period of 1.5 h using ethanol : water (1 : 1, v/v) as the complexation medium. The complex was compressed into orally disintegrating tablet. The drug release from the complex was about 2.5% in 120 s in 5 ml of pH 6.8 phosphate buffer which has been used to mimic the salivary fluid volume and pH. Dissolution studies using 500 ml of 0.1 N HCl at 50 rpm in USP Apparatus II released 92% in 5 min, indicating complete drug release from the complex in the stomach. Resinate was tasteless while the fabricated ODTs were pleasantly tasting without any bitterness of drug as confirmed by the taste panel.

Freeze-Drying of Proteins in Glass Solids Formed by Basic Amino Acids and Dicarboxylic Acids

Abstract: The purpose of this study was to produce and characterize glass-state amorphous solids containing amino acids and organic acids that protect co-lyophilized proteins. Thermal analysis of frozen solutions containing a basic amino acid (e.g., L-arginine, L-lysine, L-histidine) and a hydroxy di- or tricarboxylic acid (e.g., citric acid, L-tartaric acid, DL-malic acid) showed glass transition of maximally freeze-concentrated solute at temperatures (T′g) significantly higher than those of the individual solute solutions. Mixing of the amino acid with some dicarboxylic acids (e.g., oxalic acid) also suggested an upward shift of the transition temperature. Contrarily, combinations of the amino acid with monocarboxylic acids (e.g., acetic acid) had T′gs between those of the individual solute solutions. Co-lyophilization of the basic amino acids and citric acid or L-tartaric acid resulted in amorphous solids that have glass transition temperatures (Tg) higher than the individual components. Mid- and near-infrared analysis indicated altered environment around the functional groups of the consisting molecules. Some of the glass-state excipient combinations protected an enzyme (lactate dehydrogenase, LDH) from inactivation during freeze-drying. The glass-state excipient combinations formed by hydrogen-bonding and electrostatic interaction network would be potent alternative to stabilize therapeutic proteins in freeze-dried formulations.

Diketopiperazine alkaloids from a deep ocean sediment derived fungus Penicillium sp.

Abstract: Five new diketopiperazine alkaloids, brevicompanines D-H (3-7), together with two known analogs, allo-brevicompanine B (1) and fructigenine B (2), were isolated from a deep ocean sediment derived fungus Penicillium sp. Their structures were established by spectroscopic methods including 2D NMR and chiral HPLC analysis. Compounds 4 and 7 inhibited lipopolysaccharide (LPS)-induced nitric oxide production in BV2 microglial cells.

Design, Synthesis and Biological Evaluation of Hydroxy- or Methoxy-Substituted Phenylmethylenethiosemicarbazones as Tyrosinase Inhibitors

Abstract: A series of hydroxy- or methoxy-substituted phenylmethylenethiosemicarbazones were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. The results demonstrated that most of target compounds had remarkable inhibitory activities on mushroom tyrosinase. Interestingly, compound 2h was found to be the most potent tyrosinase inhibitor with IC50 value of 0.18 μM. The possible interaction mode between compound 2h and tyrosinase was proposed. In addition, the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities of select compounds (IC50<10.0 μM) were also investigated. Compounds 2d, 2e, 2h, 2i and 2l exhibited more potent DPPH radical scavenging activity than well-known antioxidants ascorbic acid (Vc) and tertiary butyl hydroquinone (TBHQ). These results suggested that such compounds might be utilized for the development of new candidate for treatment of dermatological disorders.