Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Volume 54, Issue 11
Displaying 1-26 of 26 articles from this issue
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Review
  • Trace Determination of Steroids Causing Age-Related Diseases Using LC/MS Combined with Detection-Oriented Derivatization
    Tatsuya Higashi
    2006 Volume 54 Issue 11 Pages 1479-1485
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1479
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    With the rapid shift to an aging society in Japan, age-related diseases, such as osteoporosis, dementia and cancer, are sharply increasing. The measurement of steroids related to these diseases in biological fluids and tissues is useful for elucidation of the nature, diagnosis and treatment of such diseases. LC/MS is considered to be the most promising method for this purpose due to its specificity and versatility, but it sometimes does not demonstrate the required sensitivity for trace amounts of steroids, because steroids have a rather low response using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). To overcome this problem, the author developed detection-oriented derivatization procedures for steroids in LC/MS. For ESI-MS, introduction of a permanently charged moiety is effective. Based on this, 2-hydrazino-1-methylpyridine was developed and used in monitoring prostatic 5α-dihydrotestosterone, a good index for the follow-up of patients affected by prostate cancer under androgen deprivation therapy and salivary dehydroepiandrosterone, which is now often designated as an anti-aging hormone. A proton-affinitive Cookson-type reagent, 4-[2-(6,7-dimethoxy-4-methyl-3-oxo-3,4-dihydroquinoxalyl)ethyl]-1,2,4-triazoline-3,5-dione, was used for the determination of 1α-hydroxyvitamin D3 [1α(OH)D3], a synthetic prodrug of the active form of vitamin D3, in human plasma, and this new LC/positive-APCI-MS method enabled the pharmacokinetic study of 1α(OH)D3 in humans. Electron-capture APCI-MS based on derivatization with 2-nitro-4-trifluoromethylphenylhydrazine was used for the analysis of neurosteroids, which affect brain excitability through action at the neurotransmitter receptors. With this method, the stress-induced rapid biosynthesis of pregnane-type neurosteroids in rat brains was demonstrated.
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Regular Articles
  • Particle Design of Three-Component System for Sustained Release Using a 4-Fluid Nozzle Spray-Drying Technique
    Richer Chen, Hirokazu Takahashi, Hirokazu Okamoto, Kazumi Danjo
    2006 Volume 54 Issue 11 Pages 1486-1490
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1486
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    We prepared composite particles of acetaminophen (Act) with chitosan (Cht) and hydroxypropylmethylcellulose phthalate (HPMCP) as a carrier using a newly developed 4-fluid nozzle spray-dryer. Cht dissolves in acid solutions and forms a gel, but it is insoluble in alkaline solutions. On the other hand, HPMCP is insoluble in acid solutions, but it dissolves in alkaline solutions. Therefore, we tested a preparation of controlled release composite particles using the characteristics of these carriers. Act and Cht mixtures in prescribed ratios were dissolved in an acid solution. Composite particles of Act and HPMCP in prescribed ratios were dissolved in alkaline solutions. We evaluated the composite particles of the three components (Act, Cht, and HPMCP) by preparing solid dispersions using a 4-fluid nozzle spray-dryer. Observation of particle morphology by scanning electron microscopy (SEM) revealed that the particles from the spray-drying process had atomized to several microns and had all become spherical. We investigated the physical properties of the composite particles by powder X-ray diffraction, differential scanning calorimetry, and dissolution rate analysis to clarify the effects of crystallinity on the dissolution rate. Powder X-ray diffraction peaks and the heat of fusion of Act in the spray-dried samples decreased in proportion to the carrier content, indicating that the drug was amorphous. These results indicate that the Act–Cht–HPMCP system formed a solid dispersion. Furthermore, we investigated the interaction between the drug and the carrier using FT-IR analysis. FT-IR spectroscopy of the Act solid dispersions suggested that the Act carbonyl and Cht amino groups formed a hydrogen bond. On the other hand, interaction by hydrogen bond was observed between the carbonyl group of HPMCP with the amino group of Act. In the three-component Act–Cht–HPMCP system, the 4-fluid nozzle spray-dried preparation with a mixing ratio of 1 : 2.5 : 2.5 obtained sustained release preparation in all pH test solutions.
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  • Comparative Study of Chemical Constituents of Rhubarb from Different Origins
    Katsuko Komatsu, Yorinobu Nagayama, Ken Tanaka, Yun Ling, Shao-Qing Ca ...
    2006 Volume 54 Issue 11 Pages 1491-1499
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1491
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    A comparative study of the pharmacologically active constituents of 24 rhubarb samples, which were identified genetically as Rheum tanguticum, 3 intraspecies groups of R. palmatum and R. officinale, was conducted using reversed-phase high performance liquid chromatography (HPLC) methods. Thirty compounds belonging to anthraquinones, anthraquinone glucosides, dianthrones, phenylbutanones, stilbenes, flavan-3-ols, procyanidins, galloylglucoses, acylglucoses, gallic acid, and polymeric procyanidins were analyzed quantitatively. The drug samples derived from the same botanical source showed similar chromatographic profiles, and the comparable specific shape that appeared in the 10-directed radar graphs constructed on the basis of the results of quantitative analysis indicated the relationship between chemical constituent patterns and genetic varieties of rhubarb samples.
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  • Optimization and Physicochemical Characterization of Thermosensitive Poloxamer Gel Containing Puerarin for Ophthalmic Use
    Hongyi Qi, Li Li, Chunyan Huang, Wenmin Li, Chunjie Wu
    2006 Volume 54 Issue 11 Pages 1500-1507
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1500
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    The purpose of this study was to systematically optimize an ophthalmic thermosensitive poloxamer analogs gel containing puerarin that was a free flowing liquid below the room temperature and could shift to a gel with an eligible gel strength and bioadhesive force in physiological condition (dilution by the simulated tear fluid and at 35.0 °C). A two-factor, five-level central composite design (CCD) was employed to the optimization procedure. The effect of formulation variables (the w/v concentration of poloxamer 407 (X1) and poloxamer 188 (X2)) on a number of response variables (the gelation temperature before (Y1) and after (Y2) the simulated tear fluid diluted, the difference between them (Y3)) was systemically investigated. A second order polynomial equation was fitted to the data. The resulting equation and response surface plots were used to predict the responses in the optimal region. Finally, 21.0% (w/v) poloxamer 407 and 5.0% (w/v) poloxamer188 were chosen as the optimal poloxamer gel matrix. The influence of the other ingredients on the physicochemical properties of the formulation was also investigated. Hydroxypropyl-β-cyclodextrin (HPCD) enhanced the gelation temperature and reduced the gel strength and the bioadhesive force, while puerarin and benzalkonium chloride (BC) had a comparatively smaller influence. All the isotonicity agents studied had the gelation temperatures lowered, and the gel strengths and the bioadhesive forces enhanced. But only sodium chloride appears to be a promising isotonicity agent for the poloxamer gel containing puerarin, HPCD and BC.
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  • Novel Approach to DPI Carrier Lactose with Mechanofusion Process with Additives and Evaluation by IGC
    Michiko Kumon, Masahiko Suzuki, Akira Kusai, Etsuo Yonemochi, Katsuhid ...
    2006 Volume 54 Issue 11 Pages 1508-1514
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1508
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    The effect of lactose carrier surface property on the inhalation profile of dry powder inhaler (DPI) was evaluated using a micronized drug (Compound A) by inverse gas chromatography (IGC). Mechanofusion with magnesium stearate (Mg-St) or sucrose stearate increased the fine particle fraction (FPF), considered to be due to decrease in the interaction between Compound A and the lactose carrier. The effect of Compound A concentration on FPF was smaller in mechanofusion-processed lactose compared to intact lactose, especially when processed with Mg-St. The relationship between the IGC parameters of the lactose and FPF was also investigated. FPF increased as both the dispersive component of the surface energy and acidity similarity between the lactose carriers and Compound A increased. Although further investigation is necessary, it could be suggested that acidity similarity decreases the interaction between Compound A and lactose, thus contributing to the increase in the FPF. In conclusion, (1) mechanofusion with Mg-St or sucrose stearate could be an effective method to improve FPF of a DPI drug formulation; (2) IGC would be a valuable method to investigate the interaction between a drug and the DPI carrier; and (3) a relationship between surface acidity and inhalation profile was suggested.
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  • 4-(Pyrrolidinyl)methoxybenzoic Acid Derivatives as a Potent, Orally Active VLA-4 Antagonist
    Jun Chiba, Shin Iimura, Yoshiyuki Yoneda, Yuichi Sugimoto, Takao Horiu ...
    2006 Volume 54 Issue 11 Pages 1515-1529
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1515
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    A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50=1.6 nM each) and moderate lipophilicity (Log D=2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.
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  • Structures of New Flavonoids, Erycibenins D, E, and F, and NO Production Inhibitors from Erycibe expansa Originating in Thailand
    Toshio Morikawa, Fengming Xu, Hisashi Matsuda, Masayuki Yoshikawa
    2006 Volume 54 Issue 11 Pages 1530-1534
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1530
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    A new flavanol, erycibenin D, and two new flavans, erycibenins E and F, were isolated from the stems of Erycibe expansa originating in Thailand. The structures of new flavonoids were elucidated on the basis of chemical and physicochemical evidence. In addition, the inhibitory activities of the isolated constituents from E. expansa on lipopolysaccharide-activated nitric oxide production in mouse peritoneal macrophages were examined. Among the principal constituents, two isoflavones, clycosin (IC50=13 μM) and erythrinin B (18 μM), and two rotenoids, deguelin (26 μM) and rotenone (27 μM), were found to show potent inhibitory activity.
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  • Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors V. A Series of New Derivatives Containing a Spiro[imidazo[1,2-a]pyrazine-2(3H),4′-piperidin]-5(1H)-one Scaffold
    Fumihiko Saitoh, Takafumi Mukaihira, Hidemitsu Nishida, Tsutomu Satoh, ...
    2006 Volume 54 Issue 11 Pages 1535-1544
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1535
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    We have already reported unique compounds containing a N,O-spiro acetal structure as an orally active factor Xa (FXa) inhibitor. This time, we described a N,N-spiro acetal structure as an analogue of the N,O-spiro acetal structure for an orally active FXa inhibitor. The synthesis of these analogues could be achieved in a similar fashion to the N,O-spiro acetal synthesis. Consequently, FXa inhibitory activity was increased and more active compounds could be found (M58163: IC50=0.61 nM, M58169: IC50=0.58 nM). Additionally, the absolute configuration could be determined by X-ray crystallography analysis (M58169: (R)-config.).
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  • Structures of New Cucurbitane-Type Triterpenes and Glycosides, Karavilagenins and Karavilosides, from the Dried Fruit of Momordica charantia L. in Sri Lanka
    Seikou Nakamura, Toshiyuki Murakami, Junko Nakamura, Hisanori Kobayash ...
    2006 Volume 54 Issue 11 Pages 1545-1550
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1545
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    Three new cucurbitane-type triterpene called karavilagenins A, B, and C and five new cucurbitane-type triterpene glycosides called karavilosides I, II, III, IV, and V were isolated from the dried fruit of Sri Lanka Momordica charantia L. (Cucurbitaceae) together with two known cucurbitane-type triterpenes, 19(R)-methoxy-5β,19-epoxycucurbita-6,23-dien-3β,25-diol and 5,19-epoxycucurbita-6,23-diene-3,25-diol, and nine known cucurbitane-type triterpene glycosides, goyaglycosides-b, -c, and -d, and momordicosides F1, F2, G, I, K, and L. The structures of karavilagenins and karavilosides were elucidated on the basis of chemical and physicochemical evidence.
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  • Glycosides of 14,15-Seco and 13,14:14,15-Disecopregnanes from the Roots of Cynanchum sublanceolatum
    Tsutomu Warashina, Tadataka Noro
    2006 Volume 54 Issue 11 Pages 1551-1560
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1551
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    Thirty-two new 13,14-seco and 13,14:14,15-disecopregnane glycosides were obtained from the roots of Cynanchum sublanceolatum (Asclepiadaceae). These glycosides were confirmed to be possessing five known compounds, cynajapogenin A, glaucogenin-A, 13-hydroxycynajapogenin A, 2α-hydroxyanhydrohirundigenin, atratogenin A and one new pregnane, 13-epi-cynajapogenin A, as their aglycones, using both spectroscopic and chemical methods.
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  • Solubility Prediction of Drugs in Water–Polyethylene Glycol 400 Mixtures Using Jouyban–Acree Model
    Abolghasem Jouyban
    2006 Volume 54 Issue 11 Pages 1561-1566
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1561
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    A numerical method is proposed for predicting solubility of drugs in water–PEG 400 mixtures based on the Jouyban–Acree cosolvency model. The accuracy of the proposed method is evaluated by computing mean percentage deviation (MPD) and compared with that of log-linear model of Yalkowsky. The overall MPDs of the Jouyban–Acree model and the most accurate version of Yalkowsky's model are 39.8 (±46.7) % and 175.8 (±266.4) %, respectively, and the mean difference is statistically significant (p<0.0005). The proposed method produces acceptable residual distribution and the probability of solubility prediction with residual log of solubility <0.5 unit is 0.86. The applicability of the proposed method could be extended for predicting the solubility of drugs in water–PEG 400 mixtures at various temperatures. The impact of various log P values computed using different software is also studied and the results of ANOVA revealed that there are no significant differences between the accuracy of the predicted solubilities employing various log P values.
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  • Synthesis and Anti-tumor Activity of a Fluorinated Analog of Medroxyprogesterone Acetate (MPA), 9α-Fluoromedroxyprogesterone Acetate (FMPA)
    Natsuko Murata, Shiho Fujimori, Yoshitatsu Ichihara, Yoshio Sato, Take ...
    2006 Volume 54 Issue 11 Pages 1567-1570
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1567
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    We synthesized 9α-fluoromedroxyprogesterone acetate (FMPA) in order to test whether it is a more potent anti-angiogenic agent than medroxyprogesterone acetate (MPA), which has been widely used as a therapeutic agent for breast and endometrium cancers. FMPA was previously synthesized in 10 steps (total yield: 1%). An efficient synthesis of FMPA has been achieved in 6 steps (total yield: 12%). We examined the anti-tumor effect of FMPA, complexed with dimethyl-β-cyclodextrin (DM-β-CyD), on rat mammary carcinomas induced by 7,12-dimethylbenz[a]anthracene (DMBA). FMPA showed great anti-tumor effect on DMBA-induced rat mammary carcinomas.
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  • Oxidative Photo-Decarboxylation in the Presence of Mesoporous Silicas
    Akichika Itoh, Tomohiro Kodama, Yukio Masaki, Shinji Inagaki
    2006 Volume 54 Issue 11 Pages 1571-1575
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1571
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    FSM-16, a mesoporous silica, was found to catalyze oxidative photo-decarboxylation of α-hydroxy carboxylic acid, phenyl acetic acid derivatives and N-acyl-protected α-amino acids to afford the corresponding carbonyl compounds. Furthermore, FSM-16 proved to be re-usable by re-calcination at 450 °C after the reaction.
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  • Function of an N-Heterocyclic Carbene Ligand Based on Concept of Chiral Mimetic
    Takafumi Arao, Kei Sato, Kazuhiro Kondo, Toyohiko Aoyama
    2006 Volume 54 Issue 11 Pages 1576-1581
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1576
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    Function of a new N-heterocyclic carbene ligand based on the concept of a chiral mimetic is described. With (4R,5R)-4,5-diphenyl-1,3-dialkyl-4,5-dihydro-3H-imidazol-1-ium tetrafluoroborates as N-heterocyclic carbene precursors, Rh-catalyzed enantioselective arylation (up to 27% ee) of aromatic aldehydes with arylboronic acids and Pd-catalyzed enantioselective intramolecular α-arylation (up to 66% ee) of N-(2-bromoaryl)-N-alkyl-2-arylpropanamides are investigated.
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  • Xylogranatins A—D, New Mexicanolides from the Fruit of a Chinese Mangrove Xylocarpus granatum
    Jun Wu, Si Zhang, Minyi Li, Yuan Zhou, Qiang Xiao
    2006 Volume 54 Issue 11 Pages 1582-1585
    Published: 2006
    Released on J-STAGE: November 01, 2006
    DOIhttps://doi.org/10.1248/cpb.54.1582
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    Four new mexicanolides with a Δ14,15 double bond, named xylogranatins A and D (1—4), were isolated from the fruit of a Chinese mangrove Xylocarpus granatum, together with two known 8,9,30-phragmalin ortho esters, xyloccensins P and Q. Their structures were elucidated on the basis of spectroscopic data, especially 2D NMR techniques including HSQC, HMBC and NOESY.
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Notes
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