YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
123 巻, 1 号
選択された号の論文の5件中1~5を表示しています
Reviews
  • 水谷 暢明
    2003 年 123 巻 1 号 p. 1-8
    発行日: 2003/01/01
    公開日: 2003/02/19
    ジャーナル フリー
    Cysteinyl leukotrienes (CysLTs: LTC4, LTD4, and LTE4) are a family of potent inflammatory mediators that appear to contribute to the pathophysiologic features of allergic rhinitis. Because treatment with a CysLT1 receptor antagonist and a 5-lipoxygenase inhibitor modified allergen-induced nasal blockage in patients with allergic rhinitis, and CysLTs were detected in nasal cavity lavage fluid, it has been suggested that CysLTs act as significant inflammatory mediators in allergic rhinitis. The role of CysLTs was evaluated in our experimental allergic rhinitis model in sensitized guinea pigs which shows biphasic nasal blockage, sneezing and nasal hyperresponsiveness to LTD4 induced by repetitive inhalation challenge with Japanese cedar pollen. In this model, the CysLT1 receptor antagonist pranlukast suppressed the late-phase nasal blockage but not early blockage and sneezing. Nasal hyperresponsiveness (nasal blockage) to LTD4 was largely blocked by pranlukast, naphazoline, and Nω-nitro-L-arginine-methyl ester. The results demonstrate that nasal blockage induced by CysLTs is mainly due to dilatation of nasal blood vessels, which can be induced by the nitric oxide produced through CysLT1 receptor activation. On the other hand, when pollen inhalation challenge was performed in the presence of nasal hyperresponsiveness, antigen-induced biphasic nasal blockage and sneezing were considerably enhanced and CysLTs contributed to both symptoms, suggesting that nasal hyperresponsiveness induces aggravation of antigen-induced nasal symptoms. The results presented in this study further suggest that our model is a good representative of human allergic rhinitis and offer evidence that CysLTs are chemical mediators mainly responsible for allergic nasal symptoms.
  • Katsumi NISHIMURA, Kiyoshi TOMIOKA
    原稿種別: Review
    2003 年 123 巻 1 号 p. 9-18
    発行日: 2003/01/01
    公開日: 2003/02/19
    ジャーナル フリー
    As a part of our studies aimed at asymmetric catalytic reactions by using an external chiral ligand, we have developed a catalytic asymmetric addition reaction of an arylthiol to α,β-unsaturated esters under the control of an external chiral ligand. The characteristic of our technology is a double activation of a thiol by lithiation and chelate formation with a chiral tridentate amino diether ligand, which simultaneously and effectively controls a stereochemistry of the reaction. One significant feature of an arylthiol is a bulky 2-substitution on aryl group, which enables the formation of a really reactive monomeric thiolate species. s-Cis conformation and capability of electron lone pair-differentiating coordination of a carbonyl oxygen to lithium are structural requirements of the substrates for high enantioselectivity. The enantioselectivity came up to 97% under the cited conditions. Asymmetric protonation of a transient enolate, generated by conjugate addition of a lithium thiolate to an enoate, was also realized. The stereochemistry of the protonation was controlled by the conformation of initially formed transient enolate in a 1,2-asymmetric induction manner. This technology enabled the asymmetric synthesis of (S)-naproxene. Stereoselective tandem C-S and C-C bond-forming reaction was developed as a logical extension by trapping the transient enolate intermediate with an aldehyde as a carbo-electrophile in the presence of phenylthiotrimethylsilane as an equilibrium-shift reagent. This tandem reaction was extended to a stereoselective cyclization of ω-oxo-α,β-unsaturated esters initiated by a lithium thiolate. Stereoselectivity of both tandem inter- and intramolecular reaction is predictable by an allylic strain-controlled conformation model of the enolate, in which an approach of aldehyde takes place anti to C-S bond through coordination of an aldehyde oxygen to lithium. Total synthesis of (−)-neplanocin A was achieved by using the tandem cyclization as a key tool for the direct construction of a five-membered carbocycle where every carbon is functionalized.
  • 伊藤 裕子
    2003 年 123 巻 1 号 p. 19-24
    発行日: 2003/01/01
    公開日: 2003/02/19
    ジャーナル フリー
    One of the major roles of public health agencies is to ensure safe products for consumers through analysis of residual antibiotics and antibacterials in livestock products. In this study, the analytical methods were established for tetracyclines (TCs), penicillins (PCs), and sulphonamides (SAs), which are widely used as veterinary drugs in livestock. Taking into consideration the inspection systems used by prefectural governments, UV-HPLC, which is commonly used in health centers, was selected as the determination method, and LC/MS/MS, which is used for highly sensitive analyses, was employed as a confirmation method. Based on the physicochemical features of TCs, PCs, and SAs, detailed examinations of the solid-phase extraction cartridge clean-up and analytical conditions were carried out. A simultaneous confirmation method for four types of TCs in bovine tissues, both the simultaneous determination method and the highly sensitive identification method of six types of weakly acidic PCs in bovine tissues, and the simultaneous determination method of SAs in animal liver and kidney were established. The development of the analytical method for PCs is described in detail in this paper. The combined use of a simple and reproducible determination method and the highly sensitive and precise confirmation of residual antibiotics and antibacterials in livestock products was successfully established for the inspection system. This should provide high-quality analysis and ensure safe product improvements.
Regular Articles
  • 市原 英明, 永見 英明, 山本 圭一, 松本 陽子, 上岡 龍一
    2003 年 123 巻 1 号 p. 25-34
    発行日: 2003/01/01
    公開日: 2003/02/19
    ジャーナル フリー
    Prolonged survival was seen in a carcinoma model in mice intraperitoneally inoculated with B-16 melanoma cells after the intraperitoneal treatment with hybrid liposomes composed of L-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylenedodecyl ether (C12(EO)n, n=10 and 23 respectivery) which had a uniform and stable structure. No drug was administered. The therapeutic effects of the single-component liposomes composed of lipids with a variety of hydrophilic head groups and different hydrophobic alkyl chains were investigated. Markedly prolonged survival (248%) of mice was achieved after treatment with DMPC liposomes. However, DMPC liposomes have the disadvantage of an unstable structure, requiring daily sonication. On the other hand, no life-prolonging effects or toxicity occured with the admistration of the other single-component liposomes employed in this study. Next, we successfully prepared stable, uniform liposomes composed of 90mol% DMPC and 10mol% C12(EO)n (n=10 and 23, respectively), which have diameters of 70nm and 100nm, respectively. Interestingly, prolonged survival (173º%) of mice was achieved after t;reatment with hybrid liposomes of 90mol% DMPC/10mol% C12(EO)n (n=10 and 23). Finally, we conducted toxicity tests using normal rats to determine hybrid liposome stability. There were no abnormal findings in blood chemistry or relative organ weights at autopsy of normal rats after hybrid liposome administration. In addition, hybrid liposomes were metabolized in the liver after intravenous administration to normal mice. These results suggest that hybrid liposomes could be used as a new single chemotherapeutic agent in the treatment of carcinoma with no side effects.
  • Noriyasu FUKUOKA, Toyohisa TSUKAMOTO, Junji UNO, Michio KIMURA, Shushi ...
    原稿種別: Regular Article
    2003 年 123 巻 1 号 p. 35-42
    発行日: 2003/01/01
    公開日: 2003/02/19
    ジャーナル フリー
    The effects of concomitant antiepileptic drugs on the serum carbamazepine concentration (Ct) were analyzed quantitatively. Primidone (PRM), phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), zonisamide (ZNS), clonazepam (CZP), and ethosuximide (ETS) were coadministered with carbamazepine (CBZ). Routine therapeutic drug monitoring data, obtained from epileptic patients who were treated with the repetitive oral administration of CBZ fine granules/tablets, were used for the analysis. A total of 119 patients were administered CBZ alone, and 91, 39, 19, and 6 patients were coadministered one, two, three, and more than four different antiepileptic drugs, respectively. Using the data obtained from the patients administered CBZ alone, Ct could be expressed approximately as a function of the daily dose per extracellular water volume (D/VECW) as Ct=A (D/VECW)B (A, B: parameter). By comparing the regression line on logCt vs. log(D/VECW) for CBZ alone with that for CBZ plus another concomitant drug, Ct was thus found to be affected at each definite ratio by PB and PHT, but not by VPA and ZNS. We postulated a model showing that Ct is affected by each concomitant antiepileptic drug i at each definite ratio. We defined the parameter Ri(i=1, 2, …, 7) representing the effect of each concomitant antiepileptic drug on Ct. A linear polynomial expression, in which both members of this model are converted into common logarithms, was used for a multiple regression analysis. The analysis clarified that PB and PHT lowered Ct to 0.770 and 0.710 the value of CBZ alone, respectively. On the other hand, VPA and ZNS did not affect Ct. The number of patients coadministered PRM, CZP, and/or ETS was not sufficient to detect the effect on Ct based on a test of significance. In the case of the addition or discontinuation of concomitant antiepileptic drugs in the same patient, the estimated Ct values were calculated using the value of each Ri and compared with the measured Ct values. Both values were in good agreement, and thus our results appear valid.
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