YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
112 巻, 9 号
選択された号の論文の9件中1~9を表示しています
  • 大村 貞文, 森本 繁夫, 長手 尊俊, 安達 孝, 河野 喜郎
    1992 年 112 巻 9 号 p. 593-614
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    A series of O-alkylated derivatives of erythromycin (EM) has been prepared and their biological properties were evaluated. Among them, clarithromycin (CAM, 6-O-methylerythromycin) exhibits most potent in vitro and in vivo antibacterial activities, higher acid-stability than EM and favorable pharmacokinetic properties as an antibiotic. CAM was originally synthesized via methylation of 2'-O, 3'-N-bis (benzyloxycarbonyl)-N-demethylerythromycin in low yield, because of the less selectivity of 6-O-methylation. The selective 6-O-methylation was achieved using the erythromycin 9-oxime derivative as a key intermediate. By the further investigation on the protective groups of 9-oxime and desosamine moiety, the production process of CAM on an industrial scale has been established via methylation of 2', 4"-O-bis (trimethylsilyl) erythromycin 9-[O-(1-isopropoxycyclohexyl) oxime] in more than 45% overall yield. CAM has the same antibacterial spectra as EM and is active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, Mycoplasma and Chlamydia. The activity of CAM against clinical isolates was 1 to 16 times higher than that of EM. The efficacies of CAM were 6 to 15 times superior to those of EM against systemic infections due to Gram-positive bacteria in mice. CAM also showed more potent therapeutic efficacies than EM against respiratory tract infections caused by S. pneumoniae and H. influenzae. CAM was well absorbed after oral administration, and its distribution to various tissues was significantly higher than that of EM in animals. The level of CAM in the lung was extremely high, which accounted 69 times that of EM. CAM was found to be distributed predominantly in the alveolar wall, especially in the alveolar epithelial cells, by microautoradiography. After oral administration in human, the serum level and urinary excretion of CAM were 5 and 20 times higher than those of EM, respectively. The major and active metabolite of CAM in human, (14R)-14-hydroxyclarithromycin, existed in significant quantity in the serum and urine, suggesting that the metabolite contributes to the excellent clinical efficacy of CAM. This paper describes the synthesis, structure-activity relationships, antibacterial activities, metabolism and clinical efficacies of CAM, a new macrolide antibiotic.
  • 田代 千秋, 湯浅 修二, 福田 武美
    1992 年 112 巻 9 号 p. 615-621
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    Four phenolic metabolites of (±)-3-chloro-5-[3-(2-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydroimidazo [1, 2-α] pyridine-3-spiro-4'-piperidino) propyl]-10, 11-dihydro-5H-dibenz [b, f] azepine (mosapramine), a new antipsychotic drug, were synthesized in order to determine their chemical structures. Pharmacological activities of the three main metabolites were compared with those of mosapramine. The activities of the metabolites were far less potent than those of mosapramine.
  • 粂 昌治, 久保田 忠俊, 木村 靖雄, 中清水 弘, 元川 清司
    1992 年 112 巻 9 号 p. 622-637
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    The synthesis, antibacterial activity and oral absorbability of 7β-[2-(R)-amino-2-phenylacetamido]-3-(1H-1, 2, 3-triazol-4-yl) methylthiomethyl-3-cephem-4-carboxylic acid (1a) and related compounds (1b-p and 2) are described. The replacement of 1, 2, 3-triazole at the C-3 position of 1a with other heteroaromatics such as 1, 2, 4-triazole, imidazole and so on decreased its oral absorbability in mice (1b-j). The oral absorbability was also influenced by the spacer length between C-3 of cephem nucleus and C-4 of 1, 2, 3-triazole. The quantitative relationship between the bioavailability and the spacer length of cephalosporins (1a and 1k-p) is discussed. These results suggest that 1, 2, 3-triazole in the side chain at the C-3 position of cephems plays an important role in good oral absorption through its interaction with the transport system of small intestine.
  • 難波 恒雄, 関谷 幸治, 門田 重利, 服部 征雄, 片山 和憲, 小泉 保
    1992 年 112 巻 9 号 p. 638-644
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    The effects of Senkyu (Cnidii Rhizoma and Ligustici chuanxiong Rhizoma) on the drug skin penetration were studied to clarify its effectivity as the baths. Ether and methanol extracts, and some essential oils of Senkyu (i.e.ligustilide, neocnidilide and butylidenephthalide) enhanced remarkably the skin penetration of benzoic acid. Furthermore, an appreciable correlation between the enhancing ratio and the skin/donor partition coefficient of benzoic acid was observed. These facts suggest that the constituents of Senkyu influence the skin penetration by enhancing the partition coefficient.
  • 山原 條二, 畠山 祥子, 谷口 久美子, 河村 芽理, 吉川 雅之
    1992 年 112 巻 9 号 p. 645-655
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    By using the effects on HCl/ethanol-induced gastric lesions in rats, β-sesquiphellandrene (2), β-bisabolene (3), ar-curcumene (4) and 6-shogaol (5) were isolated as anti-ulcer active principles in ginger, the dried rhizoma of Zingiber officinale ROSCOE (Shokyo in Japanese) which was cultivated in Taiwan, together with nine known compounds and a new diarylheptanoid. The absolute stereostructure of the diarylheptanoid was characterized as (3S, 5S)-dihydroxy-1-(4'-hydroxy-3', 5'-dimethoxyphenyl)-7-(4"-hydroxy-3"-methoxyphenyl) heptane (15) on the basis of chemical and spectroscopic evidence which included the application of the benzoate chirality method. The pungent effects of several constituents isolated from ginger were examined.
  • 伊藤 正憲, 石原 一興, 宮本 謙一, 越浦 良三
    1992 年 112 巻 9 号 p. 656-662
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    The influence of the culture supernatants of 1000 strains of intestinal lactic acid bacteria on the growth of HeLa cells was examined. The compound from Enterococcus faecium 3463 showing the strongest cell growth inhibiting effect in these strains was isolated and identified as tyramine. The effect of tyramine was activated by the newborn bovine sera (NBS), but weakly by the fetal bovine sera (FBS). Benzylamine and β-phenethylamine also showed the NBS-dependent cell growth inhibitory effect against HeLa cells.
  • 鵜飼 茂夫, 桐木 英之, 永井 勝幸, 木方 正
    1992 年 112 巻 9 号 p. 663-668
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    The conjugates of mitomycin C (MMC) with glucuronoxylomannan (AC) from Tremella fuciformis were synthesized by the use of spacers (glycine, glycylglycine, glycylglycylglycine). In i.p.-i.p. system the antitumor activity of the conjugates (MMC-G-ACP, MMC-GG-ACP, MMC-GGG-ACP) against P388 leukemia in mice was slightly lower than that of MMC by the evaluation of life span, ILS (%). In s.c.-i.p. system the antitumor activity of the conjugates against sarcoma 180 solid tumor in mice was similar to that of MMC, except for MMC-G-ACP. The reduction of the number of leukocytes caused by MMC was suppressed by attaching MMC to AC. The conjugates did not lower the cytotoxicity of MMC against L1210 mouse leukemia cells in vitro. The release rate of MMC from the conjugates in vitro (half time of MMC release : MMC-G-ACP, 8.8h ; MMC-GG-ACP, 3.1 h ; MMC-GGG-ACP, 2.9 h) was much faster than that of MMC-dextran, and differed in the length of the spacer. The results would give useful information on macromolecular carriers in drug-delivery system.
  • 嶋林 三郎, 原田 千佳子
    1992 年 112 巻 9 号 p. 669-672
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    The kinetics of hydrolysis of monoacetoacetin (MAA ; 1, 2-dihydroxy-3-acetoacetyloxypropane) in 300 mM phosphate buffer was studied by means of high performance liquid chromatography. MAA was hydrolyzed to glycerin (Glyc) and acetoacetate (AA), the latter of which furthermore decomposed to acetone (Acet) and CO2 at high temperature. The rate constant, k1, for the reaction of MAA→AA+Glyc increased with increases in temperature and pH. On the other hand, another one, k2, for the reaction of AA→Acet+CO2 increased with an increase in temperature but showed a minimum around pH 7.5 when pH was changed at a given temperature. The activation energy for k1 was almost constant in the range of studied pHs (5-8) but the pre-exponential factor, k1, 0, increased with an increase in pH. It was concluded that the decomposition reaction of MAA is consecutive in a sequence of MAA→AA→Acet. Calculated concentrations of MAA, AA, and Acet through the obtained k1 and k2 together with a given initial concentration of MAA(=40mM) were compared with those experimentally observed on the time course of the hydrolysis. They were in good agreement with each other.
  • 松田 秀秋, 中村 信介, 田中 孝幸, 久保 道徳
    1992 年 112 巻 9 号 p. 673-677
    発行日: 1992/09/25
    公開日: 2008/05/30
    ジャーナル フリー
    Effects of water extract (UW-ext) from the leaf of Arctostaphylos uva-ursi (L.) SPRENG. (Bearberry leaf) on the antiallergic and antiinflammatory activities of dexamethazone ointment were investigated. One or 2% UW-ext ointment did not inhibit the ear swelling by picryl chloride-induced contact dermatitis (PC-CD) and carrageenin-induced paw edema. UW-ext augmented the inhibitory effect of dexamethazone ointment (0.005 or 0.025%) on these allergic and inflammatory models, but not the side effect of it. These results suggest that Bearberry leaf increases the inhibitory effect of dexamethazone on the allergic and inflammatory models.
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