Showing papers in "Archives of Pharmacal Research in 2000"
TL;DR: As the most abundant catechin in GTP extract, EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis, which may contribute to the overall chemopreventive function of E GCG itself as well as the GTP.
Abstract: Green tea polyphenols (GTP) have been demonstrated to suppress tumorigenesis in several chemical-induced animal carcinogenesis models, and predicted as promising chemopreventive agents in human. Recent studies of GTP extracts showed the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Phase II enzymes gene expression and induction of apoptosis. In the current work we compared the bioligical actions of five green tea catechins: (1) induction of ARE reporter gene, (2) activation of MAP kinases, (3) cytotoxicity in human hepatoma HepG2-C8 cells, and (4) caspase activation in human cervical squamous carcinoma HeLa cells. For the induction of phase II gene assay, (−)-epigallocatechin-3-gallate (EGCG) and (−)-epicatechin-3-gallate (ECG) potently induced antioxidant response element (ARE)-mediated luciferase activity, with induction observed at 25 μM with EGCG. The induction of ARE reporter gene appears to be structurally related to the 3-gallate group. Comparing the activation of MAPK by the five polyphenols, only EGCG showed potent activation of all three MAPKs (ERK, JNK and p38) in a dose- and time-dependent manner, whereas EGC activated ERK and p38. In the concentration range of 25 μM to 1 mM, EGCG and ECG strongly suppressed HepG2-ARE-C8 cell-growth. To elucidate the mechanisms of green tea polyphenol-induced apoptosis, we measured the activation of an important cell death protein, caspase-3 induced by EGCG, and found that caspase-3 was activated in a dose- and time-dependent manner. Interestingly, the activation of caspase-3 was a relatively late event (peaked at 16 h), whereas activation of MAPKs was much earlier (peaked at 2 h). It is possible, that at low concentrations of EGCG, activation of MAPK leads to ARE-mediated gene expression including phase II detoxifying enzymes. Whereas at higher concentrations of EGCG, sustained activation of MAPKs such as JNK leads to apoptosis. These mechanisms are currently under investigation in our laboratory. As the most abundant catechin in GTP extract, we found that EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis. These mechanisms together with others, may contribute to the overall chemopreventive function of EGCG itself as well as the GTP.
394 citations
TL;DR: The wider and narrow concentration ranges between the activation of MAPK/gene induction and caspases/cell death exhibited by phenolic compounds and isothiocyanates in mammalian cells, may reflect their respective therapeutic windowsin vivo.
Abstract: Many natural products elicit diverse pharmacological effects. Using two classes of potential chemopreventive compounds, the phenolic compounds and the isothiocyanates, we review the potential utility of two signaling events, the mitogen-activated protein kinases (MAPKs) and the ICE/Ced-3 proteases (caspases) stimulated by these agents in mammalian cell lines. Studies with phenolic antioxidants (BHA, tBHQ), and natural products (flavonoids; EGCG, ECG, and isothiocyanates; PEITC, sulforaphane), provided important insights into the signaling pathways induced by these compounds. At low concentrations, these chemicals may activate the MAPK (ERK2, JNK1, p38) leading to gene expression of survival genes (c-Fos, c-Jun) and defensive genes (Phase II detoxifying enzymes; GST, QR) resulting in survival and protective mechanisms (homeostasis response). Increasing the concentrations of these compounds will additionally activate the caspase pathway, leading to apoptosis (potential cytotoxicity). Further increment to suprapharmacological concentrations will lead to nonspecific necrotic cell death. The wider and narrow concentration ranges between the activation of MAPK/gene induction and caspases/cell death exhibited by phenolic compounds and isothiocyanates, respectively, in mammalian cells, may reflect their respective therapeutic windowsin vivo. Consequently, the studies of signaling pathways elicited by natural products will advance our understanding of their efficacy and safety, of which many may become important therapeutic drugs of the future.
279 citations
TL;DR: CYP2E1 mRNA and protein levels are altered in response to pathophysiologic conditions by hormones including insulin, glucagon, growth hormone, and leptin, and growth factors including epidermal growth factor and hepatocyte growth factor, providing evidence that CYP2E 1 expression is under tight homeostatic control.
Abstract: Cytochrome P450 (CYP) 2E1 catalyzes the metabolism of a wide variety of therapeutic agents, procarcinogens, and low molecular weight solvents. CYP2E1-catalyzed metabolism may cause toxicity or DNA damage through the production of toxic metabolites, oxygen radicals, and lipid peroxidation. CYP2E1 also plays a role in the metabolism of endogenous compounds including fatty acids and ketone bodies. The regulation of CYP2E1 expression is complex, and involves transcriptional, post-transcriptional, translational, and post-translational mechanisms. CYP2E1 is transcriptionally activated in the first few hours after birth. Xenobiotic inducers elevate CYP2E1 protein levels through both increased translational efficiency and stabilization of the protein from degradation, which appears to occur primarily through ubiquitination and proteasomal degradation. CYP2E1 mRNA and protein levels are altered in response to pathophysiologic conditions by hormones including insulin, glucagon, growth hormone, and leptin, and growth factors including epidermal growth factor and hepatocyte growth factor, providing evidence that CYP2E1 expression is under tight homeostatic control.
133 citations
TL;DR: Two neolignan compounds, magnolol and honokiol, were isolated from the stem bark of Magnolia obovata and evaluated for antifungal activity against various human pathogenic fungi and showed significant inhibitory activities against Trichophyton mentagrophytes and Candida albicans.
Abstract: Two neolignan compounds, magnolol (5,5′-diallyl-2,2′-dihydroxybiphenyl,1) and honokiol (5,5′-diallyl-2,4′-dihydroxybiphenyl,2), were isolated from the stem bark ofMagnolia obovata and evaluated for antifungal activity against various human pathogenic fungi. Compound1 and2 showed significant inhibitory activities againstTrichophyton mentagrophytes, Microsporium gypseum, Epidermophyton floccosum, Aspergillus niger, Cryptococcus neoformans, andCandida albicans with minimum inhibitory concentrations (MIC) in a range of 25–100 μg/ml. Therefore, compound1 and2 could be used as lead compounds for the development of novel antifungal agents.
119 citations
TL;DR: Five furanocoumarins including a new one were isolated from the root of Angelica dahurica by repeated silica gel column chromatography, marking the first study in which the compound2 has been isolated and identified.
Abstract: Five furanocoumarins including a new one were isolated from the root ofAngelica dahurica by repeated silica gel column chromatography. Their chemical structures were determined to be isoimperatorin (1), oxypeucedanin hydrate-3″-butyl ether (2), imperatorin (3), knidilin (4), and oxypeucedanin hydrate (5). This represents the first study in which the compound2 has been isolated and identified. The long-range coupling (5
J) in the1H-NMR spectrum observed in the linear furanocoumarin skeleton was also investigated in detail.
106 citations
TL;DR: The data confirm that TCTP is a novel family of Ca2+-binding protein and this binding domain did not show any peculiar loop of calcium-binding motif such as CaLB domain and EF hand motif and it seems to be constituted of random coil regions neighboring the a helix.
Abstract: Translationally controlled tumor protein (TCTP), also known as lgE-dependent histamine-releasing factor, is a growth-related tumor protein Although the primary sequence of rat TCTP does not reveal any recognizable Ca2+-binding motif, previous studies have demonstrated that rat TCTP consisting of 172 amino acids is a Ca2+-binding protein However, the region of TCTP required for Ca2+ interaction has not been mapped to the molecule Here, we reported that the Ca2+ binding region of TCTP, which was mapped by using a combination of deletion constructs of rat TCTP and45Ca2+-overlay assay, was confined to amino acid residues 81–112 This binding domain did not show any peculiar loop of calcium-binding motif such as CaLB domain and EF hand motif and it seems to be constituted of random coil regions neighboring the a helix Thus, our data confirm that TCTP is a novel family of Ca2+-binding protein
95 citations
TL;DR: The acetone extract of the roots of Rhodiola sachalinensis has furnished six phenolic compounds which exhibited significant scavenging effects against DPPH free radical.
Abstract: The acetone extract of the roots of Rhodiola sachalinensis has furnished six phenolic compounds which exhibited significant scavenging effects against DPPH free radical. The structures of these compounds were identified and determined as gallic acid (1), (-)-epigallocatechin 3-O-gallate (2), kaempferol (3), kaempferol 7-O-alpha-L-rhamnopyranoside (4), herbacetin 7-O-alpha-L-rhamnopyranoside, (5) and rhodiolinin (6) by physico-chemical and spectral evidences.
94 citations
TL;DR: Among GL and its metabolites, GA and GAMG had more potentin vitro anti-platelet aggregation activity than GL and GA showed the most potent cytotoxicity against tumor cell lines and the potent inhibitory activity on rotavirus infection as well as growth ofHelicobacter pylori.
Abstract: The relationship between the metabolites of glycyrrhizin (18beta-glycyrrhetinic acid-3-O-beta-D-glucuronopyranosyl-(1-->2)-beta-D-glucuronide, GL) and their biological activities was investigated. By human intestinal microflora, GL was metabolized to 18beta-glycyrrhetinic acid (GA) as a main product and to 18beta-glycyrrhetinic acid-3-O-beta-D-glucuronide (GAMG) as a minor product. The former reaction was catalyzed by Eubacterium L-8 and the latter was by Streptococcus LJ-22. Among GL and its metabolites, GA and GAMG had more potent in vitro anti-platelet aggregation activity than GL. GA also showed the most potent cytotoxicity against tumor cell lines and the potent inhibitory activity on rotavirus infection as well as growth of Helicobacter pylori. GAMG, the minor metabolite of GL, was the sweetest.
89 citations
TL;DR: The pure compounds, sappanchalcone and brazilin, inactivated the SSAR activities in a dose dependent manner, whereas SSADH was inhibited partially by sappANcone and not by bBrazilin.
Abstract: 80% Aqueous MeOH extracts from the wood ofCaesalpinia sappan, which showed remarkable anticonvulsant activity, were fractionated using EtOAc,n-BuOH, and H2O. Among them, the EtOAc fraction significantly inhibited the activities of two GABA degradative enzymes, succinic semialdehyde dehydrogenase (SSADH) and succinic semialdehyde reductase (SSAR). Repeated column chromatographies for the fraction guided by activity test led to the isolation of the two active principal components. Their chemical structures were determined to be sappanchalcone and brazilin based on spectral data. The pure compounds, sappanchalcone (1) and brazilin (2), inactivated the SSAR activities in a dose dependent manner, whereas SSADH was inhibited partially by sappanchalcone and not by brazilin.
86 citations
TL;DR: A reversed-phase high performance liquid chromatographic method was developed to determine salidroside and tyrosol simultaneously in the Rhodiola rosea, and the optimum condition was Nova-Pak C18 as stationary phase, 6% methanol in water as mobile phase and detection at UV 225 nm.
Abstract: A reversed-phase high performance liquid chromatographic method was developed to determine salidroside and tyrosol simultaneously in theRhodiola rosea The optimum condition was Nova-Pak C18 as stationary phase, 65% methanol in water as mobile phase and detection at UV 225 nm The identification was carried out by comparing the retention, time and LC/MS spectrum of the relevant peaks with those of isolated standards The contents of salidroside and tyrosol in the samples gathered from various area in China were ranged over 13–111 mg/g and 03–22 mg/g, respectively
85 citations
TL;DR: It seems likely that the antioxidant action of tectorigenin and kaikasaponin III may alleviate the streptozotocin-induced toxicity and contribute to hypoglycemic and hypolipidemic effects.
Abstract: Tectorigenin and kaikasaponin III from the flowers of Pueraria thunbergiana showed potent hypoglycemic and hypolipidemic effects in the streptozotocin-induced diabetic rats. Intraperitoneal administration of these two compounds with 5 and 10 mg/kg, respectively, for seven days to streptozotocin-induced rats significantly reduced the blood glucose, total cholesterol, LDL- and VLDL-cholesterol and triglyceride levels when compared with those of control group. Glycitein in which 5-OH is unlinked and tectoridin (7-O-glycoside of tectorigenin) isolated from the flowers of P. thunbergiana did not improve hyperglycemia and hyperlipidemia. In addition, tectorigenin showed in vitro antioxidant effects on 1,1diphenyl-2-pirylhydrazyl (DPPH) radical, xanthine-xanthine oxidase superoxide anion radical, and lipid peroxidation in rat microsomes induced by enzymatic and non-enzymatic methods. We further found that tectorigenin and kaikasaponin III protected the Vero cell line (normal monkey kidney) from injury by hydrogen peroxide. From these findings, it seems likely that the antioxidant action of tectorigenin and kaikasaponin III may alleviate the streptozotocin-induced toxicity and contribute to hypoglycemic and hypolipidemic effects.
TL;DR: buffer extracts from Tabanus, Mylabris and Huechys showed a potent anticancer activity, and those from Catharsius, Red ant, Scorpion, Tabanus and Vespae Nidus showed a strong L-amino acid oxidase (AAO) activity as well as cytotoxicity, while buffer extracts from Apriona germari larvae showed greater/more rapid Hela cell growth than that of other insects.
Abstract: The cytotoxicity of crude insect drugs was measured using HeLa cells originating from human cervix and uterine cancer, using the dye uptake assay in order to find potential anticancer agents. Three kinds of extracts (buffer, methanol and ethylacetate) were prepared from 26 insects and used as raw materials for the activity assay. Among these, the buffer extracts from Tabanus, Mylabris and Huechys showed a potent anticancer activity, and those from Catharsius, Red ant, Scorpion, Tabanus and Vespae Nidus showed a strong L-amino acid oxidase (AAO) activity as well as cytotoxicity. In contrast, buffer extracts fromCryllotalpa orientalis andApriona germari larvae showed greater/more rapid Hela cell growth than that of other insects.
TL;DR: Brain uptake of OT was similar to that of sucrose, plasma space marker, indicating that OT has a poor BBB permeability, and in a similar manner to the opioid system, OT may play a modulatory role in antinociception.
Abstract: To establish the usefulness of oxytocin (OT) as an analgesic for women in delivery, the pharmacokinetic parameters and blood-brain barrier (BBB) permeability of [3H]OT were obtained using an intravenous injection technique or the internal carotid artery perfusion/capillary depletion (ICAP/CDM) method. Brain uptake of OT was similar to that of sucrose, plasma space marker, indicating that OT has a poor BBB permeability. Moreover, the analgesic effects of OT injected through the jugular vein on nociception were evaluated by the tail-flick method. The antinociceptive effects of OT injected at a dose of 0.2 mg/kg or 2 mg/kg were dose-dependent. In addition, the analgesic effects of OT on the CNS were unaffected by naloxone, a m-receptor antagonist. In a similar manner to the opioid system, OT may play a modulatory role in antinociception.
TL;DR: The antioxidant activity of Artemisia montana was determined by measuring the radical scavenging effect on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and inhibitory activity against free radical generation of hepatocytes (AC2F) by solvent extraction.
Abstract: The antioxidant activity ofArtemisia montana was determined by measuring the radical scavenging effect on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and inhibitory activity against free radical generation of hepatocytes (AC2F). The methanol extract ofA. montana showed strong radical scavenging activity at a concentration of 10.1 μg/ml, and thus fractionated by solvent extraction. Esculetin and luteolin 7-O-rutinoside (scolymoside) were isolated as the active principles from the EtOAc and Interphase fractions, respectively. The antioxidant activity of these compounds were comparable to that of L-ascorbic acid.
TL;DR: These compounds except vomifoliol significantly inhibited lipid peroxidation in rat liver microsome and were assigned as a new aromatic monoterpene and catechin on the basis of UV, mass, and NMR spectroscopic analyses.
Abstract: Twelve compounds with lipid peroxidation inhibitory activity were isolated from the stem bark ofE. globulus. Their structures were assigned as a new aromatic monoterpene (1) and eleven known compounds, pinoresinol (2), vomifoliol (3), 3,4,5-trimethoxyphenol 1-O-β-D-(6′-O-galloyl)glucopyranoside (4), methyl gallate (5), rhamnazin (6), rhamnetin (7), eriodictyol (8), quercetin (9), taxifolin (10), engelitin (11), and catechin (12) on the basis of UV, mass, and NMR spectroscopic analyses. These compounds except vomifoliol significantly inhibited lipid peroxidation in rat liver microsome.
TL;DR: Bioassay-guided fractionation ofCrataegus pinnatifida gave two cytotoxic ursane-type triterpenes which were identified as uvaol and ursolic acid which exhibited potent cytotoxicity activities both in murine and in human cancer cell lines.
Abstract: Bioassay-guided fractionation of Crataegus pinnatifida (Rosaceae) gave two cytotoxic ursane-type triterpenes which were identified as uvaol (1) and ursolic acid (2) by physicochemical and spectroscopic methods. 3-Oxo-ursolic acid (3) was synthesized from ursolic acid (2) by Jones method. The cytotoxic activities of these compounds were tested against murine L1210 and human cancer cell lines (A549, SK-OV-3, SK-MEL-2, XF498, and HCT15) in vitro. Compounds 1 and 2 showed moderate cytotoxicities against L1210, whereas they showed weak activities against human cancer cell lines. However, compound 3 exhibited potent cytotoxic activities both in murine and in human cancer cell lines.
TL;DR: A lectin (agglutinin, VCA) from Korean mistletoe was isolated by affinity chromatograpy on a asialofetuin-Sepharose 4B and the VCA recognized the antibody of VAAs in the Western blot analysis and ELLA system.
Abstract: A lectin (agglutinin, VCA) from Korean mistletoe (Viscum album L.coloratum) was isolated by affinity chromatograpy on a asialofetuin-Sepharose 4B. The molecular weights of A-and B-chains of VCA were differenf from those of VAAS. The VCA recognized the antibody of VAAs in the Western blot analysis and ELLA system. We also investigated the synergistic effects of the components in mistletoe by dividing the extract into different molecular weight fractions.
TL;DR: The observations showed that the immunomodulating activity of PMA increased lymphocyte proliferation and that PMA decreased antibody production from B cells, which was distinct from those of other plant-originated polysaccharides.
Abstract: The immunomodulating activity of a polysaccharide isolated fromMorus alba (PMA) root bark was examined in murine splenic lymphocytes. PMA enhanced proliferation of splenic lymphocytes in a synergistic manner in the presence of mitogens. However, PMA suppressed primary IgM antibody production, from B cells, which was activated with lipopolysaccharide, a polyclonal activator, or immunized with a T-cell dependent antigen sheep red blood cells. Our observations showed that the immunomodulating activity of PMA increased lymphocyte proliferation and that PMA decreased antibody production from B cells, which was distinct from those of other plant-originated polysaccharides.
TL;DR: In pentobarbital-anesthetized dogs, the intravenous administration of DA-8159 potentiated the increase in ICP induced by the intracavernosal SNP in a dose-related manner, suggesting that DA- 8159 has significant therapeutic potential in the treatment of erectile dysfunction.
Abstract: DA-8159, a new phosphodiesterase 5 inhibitor, was assessed for its erectogenic potential by a penile erection test in rats, the relaxation of isolated rabbit corpus cavernosum (CC), and estimation of the intracavernous pressure (ICP) in the anesthetized dog. Oral administration of DA-8159 (0.3 to 1 mg/kg) increased the number of erections in rats with increasing dosage, with the highest penile erection index at 10 mg/kg. DA-8159 induced the relaxation of phenylephrine (PHE)-induced contractions in the rabbit CC and decreased the IC50 of the nitric oxide donor sodium nitroprusside (SNP) in a dose-dependent fashion. In pentobarbital-anesthetized dogs, the intravenous administration of DA-8159 (1 approximately 300 g/kg) potentiated the increase in ICP induced by the intracavernosal SNP in a dose-related manner. These findings suggest that DA-8159 has significant therapeutic potential in the treatment of erectile dysfunction.
TL;DR: The results suggest that the suppression of NO production is mediated by the inhibitory action on the i-NOS gene expression through the inactivation of NF-κB and this sesquiterpene lactone can act as a pharmacological inhibitor of the NF-σB activation.
Abstract: To elucidate the molecular mechanisms for the suppression of LPS-induced nitric oxide (NO) production by a dehydrocostus lactone (DL) fromSaussurea lappa, we examined the preventive effect of this compound on NF-κB activation in LPS-treated RAW 264.7 macrophages and U937 human monocytic cells. The results suggest that the suppression of NO production is mediated by the inhibitory action on the i-NOS gene expression through the inactivation of NF-κB and this sesquiterpene lactone can act as a pharmacological inhibitor of the NF-κB activation.
TL;DR: The results suggest that the metabolites of phytosterols in rat feces are formed by oxidation at 3- position, saturation at 5- and 6- positions, and 17- side chain cleavage in the rat large intestine.
Abstract: β-Sitosterol, campesterol and stigmasterol have been known to the phytosterols the most frequently found in plants. Metabolism of phytosterols was investigated using rat feces and liver microsomes. Feces were collected after phytosterols (a well characterized mixture of β-sitosterol 40%, campesterol 30% and dihydrobrasicasterol) were administered orally (0.5 g/kg) to rats. Metabolites of phytosterols were identified using GC/MS. Three peaks were eluted at 12.47, 12.65, 12.87 min and had characteristic molecular ionsm/z 428, 430, 432, respectively. Three fecal metabolites were identified as androstadienedione, androstenedione, and androstanedione. No metabolites could be detected in the rat liver microsomal reaction mixture. The results suggest that the metabolites of phytosterols in rat feces are formed by oxidation at 3- position, saturation at 5- and 6- position, and 17- side chain cleavage in the rat large intestine.
TL;DR: These compounds were isolated from the leaves of Alnus hirsuta Turcz based on the spectral and physicochemical data.
Abstract: Diarylheptanoids, (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane-3-one (1, hirsutanonol), (5S)-1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-one-5-O-β-D-xylopyranoside (2, oregonin), (5R)-1,7-bis-(3,4-dihydroxyphenyl)-heptane-5-O-β-D-xylopyranoside (3), and (5R)-1,7-bis-(3,4-dihydroxyphenyl)-heptane-5-O-β-D-glucopyranoside (4) were isolated from the leaves ofAlnus hirsuta Turcz. The structures of these compounds were identified based on the spectral and physicochemical data.
TL;DR: The results suggest a possible use of GSAE in managing mast cell-dependent anaphylaxis and a significant inhibitory effect on anti-DNP IgE-induced tumor necrosis factor-α production from RPMC.
Abstract: We investigated the effect of aqueous extract ofGleditsia sinensis thorns (Leguminosae) (GSAE) on the mast cell-dependent anaphylaxis. GSAE (0.005 to 1 g/kg) also sigendently inhibited systemic anaphylaxis induced by compound 48/80 in rats. GSAE (0.1 and 1 g/kg) also significantly inhibited local anaphylaxis activated by anti-DNP IgE. When GSAE was pretreated at the same concentrations with systemic anaphylaxis, the plasma histamine levels were reduced in a dose-dependent manner. GSAE (0.001 to 1 mg/ml) dose-dependently inhibited the histamine release from rat peritoneal mast cells (RPMC) activated by compound 48/80 or anti-DNP IgE. The level of cyclic AMP in RPMC, When GSAE (1 mg/ml) was added, transiently and significantly increased about fourfold compared with that of basal cells. Moreover, GSAE (0.01 and 0.1 mg/ml) had a significant inhibitory effect on anti-DNP IgE-induced tumor necrosis factor-α production from RPMC. These results suggest a possible use of GSAE in managing mast cell-dependent anaphylaxis.
TL;DR: A chiral stationary phase of α1-acidglycoprotein, the AGP-CSP, was used to separate the enantiomers and this method appears to have applications for enantioselective pharmacokinetic studies of racemic drugs.
Abstract: In order to study the simultaneous determination of (+)- and (−)-cetirizine in human urine we have developed a chiral separation method by HPLC. A chiral stationary phase of α1-acidglycoprotein, the AGP-CSP, was used to separate the enantiomers. The pH of the phosphate buffer, as well as the content of the organic modifier in the mobile phase, markedly affected the chromatographic separation of (+)- and (−)-cetirizine. A mobile phase of 10 mmol/l phosphate buffer (pH 7.0)-acetonitrile (95∶5, v/v) was used for the urine assays. Ultraviolet absorption was monitored at 230nm and roxatidine was employed as the internal standard for quantification.
TL;DR: To demonstrate the effect of formulation conditions on the controlled release of protein from poly(lactide-co-glycolide) (PLGA) microspheres for use as a parenteral drug carrier, ovalbumin (OVA)microspheres were prepared using the W/O/W multiple emulsion solvent evaporation and extraction method.
Abstract: To demonstrate the effect of formulation conditions on the controlled release of protein from poly(lactide-co-glycolide) (PLGA) microspheres for use as a parenteral drug carrier, ovalbumin (OVA) microspheres were prepared using the W/O/W multiple emulsion solvent evaporation and extraction method. Methylene chloride or ethyl acetate was applied as an organic phase and poly(vinyl alcohol) as a secondary emulsion stabilizer. Low loading efficiencies of less than 20% were observed and the in vitro release of OVA showed a burst effect in all batches of different microspheres, followed by a gradual release over the next 6 weeks. Formulation processes affected the size and morphology, drug content, and the controlled release of OVA from PLGA microspheres.
TL;DR: The synthesis and spectral analysis of some new 1,3-dihydro-3-hydroxy-3-[2-Hydroxyimino-2-(substituted phenyl)ethyl]-2H-indol-2-ones and spiro[3H-Indol-3,5/t’-(4/t'H)-isoxazol]-2(1H)-ones and they exhibited significant antimicrobial activity especially the oximes27.
Abstract: The synthesis and spectral analysis of some new 1,3-dihydro-3-hydroxy-3-[2-hydroxyimino-2-(substituted phenyl)ethyl]-2H-indol-2-ones (21–32) and spiro[3H-indol-3,5/t’-(4/t’H)-isoxazol]-2(1H)-ones (33–44) are described. Sixteen of the synthesized compounds were screenedin vitro for their growth inhibitory activity against thirteen species of microorganisms,viz, S. aureus, S. epidermidis, S. faecalis, B. subtilis, B. cereus, E. aerogens, E. coli, P. aeruginosa, P. vulgaris, A. baumonia, A. faecalis, C. albicans andS. cervicae. Most of the compounds exhibited significant antimicrobial activity especially the oximes28 and29.
TL;DR: Quantitative structure activity relationship of the 4-substituted series shows that only STERIMOL L values are well correlated and the phenyl motif with sterically large substituent at 4-position and small substituents at 3-position may be important for their activity.
Abstract: To explore the effect of substituents on phenyl motif on sulfonyl function of novel anticancer 4-phenyl-1-benzenesulfonylimidazolidinones (1), electron donating or withdrawing substituents were introduced at 3 or 4-position and the analogs were tested agaist human lung (A549) and colon (HCT-15) cancer cell lines. Quantitative structure activity relationship of the 4-substituted series shows that only STERIMOL L values are well correlated. The increment of substituent's volume enhances the activity against both cell lines. The small substituent at 3-position additionally increases the activity. However naphthyl group in place of phenyl reduces the activity. Therefore the phenyl motif with sterically large substituent at 4-position and small substituent at 3-position may be important for their activity. Integration of these substituents' effects into the structural design led to discover the more potent analog, 4-phenyl-1-(N-acetylindoline-5-sulfonyl) imidazolidinone (1n).
TL;DR: Measured using the HPLC method on chiral column without any derivatization, the optical purity of enantiomers of metoprolol and o-demethylated metabolite3b ranged between 96–99% ee and that of enantomers of carboxylic acid metabolite4 ranged 91% eE.
Abstract: To obtain the standard compounds of metoprolol for a pharmacokinetic study, a convenient synthetic procedure to prepare enantiomers of metoprolol (3a) and its major metaboites, 2-4-(2-hydroxy-3-isopropylamino)propoxyphenylethanol (3b) and 4-(2-hydroxy-3-isopropylamino) pro-poxyphenylacetic acid (4), was developed from their respective starting materials, 4-(2-methoxyethyl)phenol (1a), 4-(2-hydroxyethyl)phenol (1b) and methyl 4-hydroxyphenylacetate (1c). These phenolic compounds (1a, b, c) were convertedin situ to their corresponding phenoxides with sodium hydroxide treatment followed by (R)- or (S)-epichlorohydrin treatment. The resulting epoxides2 were transformed to3 through reaction with isopropylamine. Ester3c was hydrolyzed to the metabolite4. Measured using the HPLC method on chiral column without any derivatization, the optical purity of enantiomers of metoprolol and o-demethylated metabolite3b ranged between 96–99% ee and that of enantiomers of carboxylic acid metabolite4 ranged 91% ee.
TL;DR: The diethyl ether extract of Isodon excisus var.coreanus exhibited significant inhibitory activity in aromatase assay, and bioactivity-guided fractionation of the extract led to the isolation of three active compounds.
Abstract: The diethyl ether extract ofIsodon excisus var.coreanus exhibited significant inhibitory activity in aromatase assay. Bioactivity-guided fractionation of the extract led to the isolation of three active compounds: inflexin (ent-1α-hydroxy-3β,6a-diacetoxykaur-16-en-11,15-dione) (1), ursolic acid (2), and ursolic acid 3-O-acetate (3).
TL;DR: Data indicated that the improvement in the purity of the Form II crystal for clarithromycin as well as a significant cost reduction is likely by the novel method.
Abstract: It is well recognized that physicochemical properties of drugs are affected by the type of polymorphic crystalline form of drugs. Clarithromycin is known to exist in at least three polymorphic crystalline forms. Since conventional means to obtain the most thermodynamically stable form (Form II) for the antibiotics is known to be associated with a low purity of the stable form, we developed a novel method to improve the purity of the crystalline form by a modification of the preparation process. The new method involved a simple recrystallization of clarithromycin in solvents having 5–12 carbon atoms (e.g., hexane and heptane) or ethers with 4–10 carbon atoms (e.g., isopropyl ether) and, thus, less likely to be associated with the problem in purity of resulting crystal. Differential scanning calorimetry and powder X-ray diffraction were used to compare the crystalline form of the resultant powder with Form II crystal prepared by the conventional method. The crystal prepared by the new method was identical to Form II crystal of the conventional method as evidenced by the lack of the exothermic peak near 110°C in differential calorimetry scan, indicating that Form II crystal could be readily prepared by the new process. Therefore, these data indicated that the improvement in the purity of the Form II crystal for clarithromycin as well as a significant cost reduction is likely by the novel method.