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抗癌剤Cyclophosphamideの肝への摂取および肝での代謝促進への試み

原田善雄

肝臓
1973年 14 巻 2 号 108-115
発行日: 1973/02/28
公開日: 2009/07/09

DOI https://doi.org/10.2957/kanzo.14.108

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制癌薬に関する薬物相互作用(第1報)

Aminopyrine，ChlorpromazineあるいはMorphine反復投与マウスにおけるCyclophosphamideの抗腫瘍作用

佐々木健一, 斉藤正明, 高柳義一

日本薬理学雑誌
1979年 75 巻 6 号 543-550
発行日: 1979年
公開日: 2007/03/29

DOI https://doi.org/10.1254/fpj.75.543

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ddY系雄マウスを用い，cyclophosphamideの単独投与あるいは他薬と併用時の抗腫瘍作用と急性毒性について検討した．抗腫瘍作用はEhrlich腹水癌細胞1×10⁶個を大腿部筋肉内に注射して15日後の固型癌の重量を測定することによって調べた．また，pentobarbitalによる睡眠時間を測定し，肝の薬物代謝酵素の活性度を知る指標とした．薬物代謝酵素誘導薬のpentobarbitalを反復投与したマウスにおいては，pentobarbitalによる睡眠時間は短縮し，cyclophosphamideによる抗腫瘍作用は強まった．これに反して，薬物代謝酵素阻害薬のSKF525Aあるいはcycloheximideはpentobarbitalによる睡眠時間を著しく延長させ，cyclophosphamideによる抗腫瘍作用を弱めた．aminopyrineあるいはchlorpromazineを反復投与したマウスにおいては，pentobarbitalによる睡眠時間は短縮し，cyclophosphamideによる抗腫瘍作用は強まった．このことからみて，aminopyrineおよびchlorpromazineは反復投与時に肝の薬物代謝酵素の活性を上昇させてcyclophosphosphamideを活性型に変換させるものと思われる．morphineの反復投与においては用量あるいは投与回数によって，pentobarbital睡眠時間やcyclophosphamideの抗腫瘍作用に対する影響に一定の傾向が認められなかった．一方，cyclophosphamideを1回投与し致死率を30日間観察した場合，aminopyrine，chlorpromazineあるいはmorphineを反復投与したマウスでは，cyclophosphamide単独よりも致死率がいずれも上昇した．
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Thiamine及びその誘導体の内耳液移行

牧本一男, 竹田禎郎, 小寺明吉

医療
1975年 29 巻 3 号 239-242
発行日: 1975/03/20
公開日: 2011/10/19

DOI https://doi.org/10.11261/iryo1946.29.239

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神経性難聴の治療としてVitamin B₁ (Thiamine)の高単位療法が広く行われている. このような臨床的重要性に鑑み³⁵S-Thiamineと³⁵S-DCET (Dicarbethoxythiamine)を使用し両物質の内耳液移行を比較検討した. すなわち, これら放射性物質を股静脈より注入しその後経時的に内リンパ, 外リンパ, 脳脊髄液について³⁵Sの放射活性を最長3時間にわたつて計測した.
³⁵S-DCETは上記の3つの体液において共に放射活性のピーク値で³⁵S-Thiamineより大であつた. ^35S-DCETの場合, それらピーク値のうちでは脳脊髄液で最も高く外リンパ, 内リンパでは共に低値を示した. この結果は以前我々が行つたグルコースの成績と異なつており, グルコースの場合ピーク値の順位は外リンパ>脳脊髄液>内リンパという順であつた. 内リンパで低値を示すことは両実験に共通した所見であつた. このように血液・内耳液間の物質輸送は複雑な諸相を呈しており今後の研究で明らかにされていくものと考えられる.
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16 神通川流域土壌復元田の実態調査 : (1)土壌の理化学性(中部支部講演会要旨)

山田信明, 岩田宗徳, 滝脇敏, 舘田修司, 小竹章

日本土壌肥料学会講演要旨集
1988年 34 巻
発行日: 1988/03/20
公開日: 2017/06/27

DOI https://doi.org/10.20710/dohikouen.34.0_288_2

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15 水田土壌の粘土鉱物組成が有機態窒素の無機化に及ぼす影響(中部支部講演会要旨)

廣川智子, 北川靖夫

日本土壌肥料学会講演要旨集
1988年 34 巻
発行日: 1988/03/20
公開日: 2017/06/27

DOI https://doi.org/10.20710/dohikouen.34.0_288_1

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制癌薬に関する薬物相互作用(第2報)免疫賦活薬投与マウスにおけるシクロホスファミドの抗腫瘍作用

佐々木健一, 斎藤正明, 高柳義一

YAKUGAKU ZASSHI
1979年 99 巻 2 号 187-191
発行日: 1979/02/25
公開日: 2008/05/30

DOI https://doi.org/10.1248/yakushi1947.99.2_187

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The antitumor activities of cyclophosphamide (CPA) on Ehrlich solid tumor in mice were examined alone and in combination with immunopotentiators. Killed Mycobacterium butyricum (MB), OK-432 (Picibanil) and lipopolysaccharide (E. coli, LPS) prolonged the pentobarbital-induced sleeping time of mice with dose-dependence. MB and LPS markedly inhibited the antitumor activity of CPA. In MB-or LPS-treated mice, the analgesic action of aminopyrine was increased and the action of codeine phosphate was decreased. These immunopotentiators may change the activity of combined drugs by inhibition of the hepatic microsomal drug-metabolizing system.
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ビタミンB₁類の安定性に関する研究(第11報) : 酸性水溶液中のO, S-Bis (alkoxycarbonyl) thiaminesの安定性

稲津邦平, 砂川成代, 山本隆一

YAKUGAKU ZASSHI
1969年 89 巻 3 号 320-330
発行日: 1969/03/25
公開日: 2008/05/30

DOI https://doi.org/10.1248/yakushi1947.89.3_320

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Analysis with an analog computer was made on the degradation of O, S-bis (ethoxycarbonyl) thiamine (I) in aqueous solution at 100° in a pH range from of 1 to 5. The analyses were based on both the results of the separate determination of the degradation products including thiamine (B₁), O-ethoxycarbonylthiamine (II), S-ethoxycarbonyl thiamine (V), 2-methyl-4-amino-5-hydroxymethylpyrimidine (III), and 2-methyl-4-amino-5-aminomethylpyrimidine (IV), and on the results previously reported for the degradation of II and V. Four different degradation routes of I were found : the two first ones are hydrolyses of -O-COOC₂H₅ and -S-COOC₂H₅ to -OH and -SH, respectively, and the other two are direct formations from I to III and to IV. At lower pH values, below or around 1.5, the reaction I→IV proceeded more easily than the other reactions and the reaction I→V was faster than the reaction I→II, where the product V was further converted to II. At the higher pH values, however, the rate of the reaction I→V was small compared with the overall degradation rate of I, and -S-COOC₂H₅ of I was hydrolysed faster than -O-COOC₂H₅ of I. These results are supported because we found relative amounts of two different O-alkoxycarbonylthiamines (B₁-O-COOR₁ and B₁-O-COOR₂) produced from O, S-bis (alkoxycarbonyl) thiamines (R₁-OOC-O-B₁-S-COOR₂). Furthermore, the stability of I was compared with the stabilities of fifteen different B₁ derivatives of acyl, a1koxycarbonyl, and disulfide types in aqueous solutions under the conditions mentioned above.
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10-chloro-11b(2-fluorophenyl)-7-(2-hydroxyethyl)-2, 3, 5, 11b-tetrahydrooxazolo-[3, 2-d][1, 4]benzodiazepine-6(7H)-one(MS-4101)のラットにおける細胞遺伝学的研究

根田公一, 山本かづみ, 佐藤春夫, 沢井正治, 石村勝正

日本薬理学雑誌
1977年 73 巻 6 号 651-656
発行日: 1977年
公開日: 2007/03/29

DOI https://doi.org/10.1254/fpj.73.651

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MS-4101の染色体異常誘発能を調べるためJCL-SD系ラットを用いて細胞遣伝学的研究を行なった．200mg/kg，500mg/kg，2,000mg/kgを経口的に単一投与および連続投与し，骨髄細胞の染色体を観察して，染色体異常を検索した．その結果MS-4101に起因すると思われる染色体異常は認められなかった．また，類似薬物であるdiazepam，nitrazepamにおいても染色体異常誘発能は認められなかった．しかし，陽性対照薬物のcyclophosphamideでは20mg/kg，50mg/kgの経口投与において骨髄細胞の染色体に，構造異常の増加が認められた．
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S-Alkoxycarbonylthiamineのラットにおける致死機構の解析

上田元彦, 川上勝, 松田三郎, 峰下銕雄

YAKUGAKU ZASSHI
1968年 88 巻 7 号 882-892
発行日: 1968/07/25
公開日: 2008/05/30

DOI https://doi.org/10.1248/yakushi1947.88.7_882

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As the so-called "mass therapy" by new thiamine derivatives are frequently carried out with some clinical improvements, it is very important to clarify the mode of acute toxicity of these thiamine derivatives. By continuous intravenous infusion of thiamine derivatives in rats under artificial respiration, it was proved that the activity in respiratory arrest decreased in the following order : O-ethoxycarbonylthiamine (OCET)>thiamine(B₁-HCI)>thiamine tetrahydrofurfuryldisulfide (TTFD)>O, S-bisethoxycarbonylthiamine (DCET)>S-butoxycarbonylthiamine (CBT)>S-ethoxycarbonylthiamine (CET)>thiamine disulfide. Even under artificial respiration, cardiac arrest was observed by the intravenous infusion of CBT and DCET in 100 mM saline solution. No cardiac arrest, however, was seen by the intravenous infusion of B₁-HCl and OCET saline solution under artificial respiration. It was proved that cardiac arrest following DCET administration was most intimately related to the DCET concentration in blood plasma, because the equimolar administration of B₁-HCl, OCET, or CET caused no cardiac arrest in rats. Twitch potentiation caused by S-alkoxycarbonylthiamine (S-CAT) in the striated muscle was considered as being one of the possible causes for weak toxicity because, marked respiratory excitement was observed by S-CAT administration. Comparing the effects of various thiamine derivatives-thiazole, thiole, and disulfide type thiamine-, it was confirmed that the twitch potentiation in the curarized rat isolated diaphragm was mainly observed when S-CAT was administered.
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S-Carbalkoxythiamine類にかんする研究 : (X)S-Carbalkoxythiamine代謝因子の酵素学的性質

森田実, 峰下銕雄

ビタミン
1966年 33 巻 1 号 76-80
発行日: 1966/01/25
公開日: 2018/02/09

DOI https://doi.org/10.20632/vso.33.1_76

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Enzymatic properties of S-carbalkoxythiamine (CAT) metabolizing factor partially purified from rabbit liver has been investigated. The factor was stable for at least 20 minutes at 50℃, while it was completely inactivated within 2 minutes at 100℃. Optimal pH for S-carbobutoxythiamine metabolism was around 7.5,but in case of O, S-dicarbethoxythiamine, the higher the pH, the more the thiamine produced. The activity was inhibited by eserine, neostigmine and heavy metal ions such as Hg^<2+> and Cu^<2+>. The final reaction products of CAT with this factor were identified as thiamine, carbon dioxide and alcohol corresponded to the alkoxy radical of CAT, so that this metabolic reaction was considered to be a hydrolytic reaction accompanied by decarboxylation, and the catalytic factor for this reaction should be classified as a hydrolase.
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体外灌流による保存条件の検討

太田宗夫, 久保田進三郎, 鵜飼卓, 吉岡敏治, 桑原倶子, 洪性徳, 阪本俊一, 藤本輝夫, 小林延行, 浜正純, 大城孟, 岡村純, 村上文夫

肝臓
1970年 11 巻 5 号 412-418
発行日: 1970/10/31
公開日: 2009/07/09

DOI https://doi.org/10.2957/kanzo.11.412

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アルキル化剤Ifosfamideに関する臨床的研究

第2編 Ifosfamideおよびその活性代謝物4-hydroxy-ifosfamideの生体内動態よりみたIfosfamideの投与法に関する検討

原田淳一

岡山医学会雑誌
1983年 95 巻 5-6 号 517-533
発行日: 1983/06/30
公開日: 2009/03/30

DOI https://doi.org/10.4044/joma1947.95.5-6_517

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A new method for quantitative analysis of ifosfamide and its active metabolite, 4-hydroxy-ifosfamide, was applied to determine the optimal mode of administration of ifosfamide. Three each of six patients with extensive bronchogenic carcinoma were given a single 40mg/kg dose of ifosfamide by either a five-minute or 60-minute intravenous infusion, with a second course of treatment 7-21 days later. Using the NaOH method, the pharmacokinetics was investigated to determine which administration schedule, the five-minute or 60-minute infusion, was preferable for the treatment of clinical malignancies. Ifosfamide was quite stable, but 4-hydroxy-ifosfamide was labile in blood samples, though immediate extraction with dichlorethane minimized the lability of 4-hydroxy-ifosfamide. The distribution volume and the transfer constant into 4-hydroxy-ifosfamide of ifosfamide were rather large, while the transfer constant for urinary excretion was rather small after the 60-minute infusion. The amount of unchanged ifosfamide excreted into urine was larger and its excretion more rapid after the five-minute infusion. As for 4-hydroxy-ifosfamide, the elimination constants and the maximum concentration in the blood were similar for both schedules, but the distribution volume was larger after the 60-minute infusion. The urinary excretion of 4-hydroxy-ifosfamide was delayed and the ratio of 4-hydroxy-ifosfamide to unchanged ifosfamide was larger after the 60-minute infusion. These results suggest that the 60-minute intravenous infusion is preferable to the five-minute intravenous infusion.
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S-Alkoxycarbonylthiamine 類の消化管運動に対する薬理学的研究

上田元彦, 松田三郎, 峰下銕雄, 武田寛

日本平滑筋学会雑誌
1969年 5 巻 2 号 108-116
発行日: 1969/06/01
公開日: 2011/03/01

DOI https://doi.org/10.1540/jsmr1965.5.108

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Peristaltic movements of dog intestine (Thiry-Vella loop), and rabbit stomach and duodenum were inhibited by the intravenous administration with higher dosage (5-25 mg/kg) of thiamine (B₁-HCl) or 0, 5-dicarbethoxythiamine (DCET), a derivative of S-Alkoxycarbonylthiamine (S-CAT). Inhibitory effects of B₁-HCI on the peristaltic movements were superior to those of POET, while propulsion of charcoal meal both in the small intestine and large intestine of mice was not affected by B₁-HCI or POET.
In the isolated intestine of rabbits, its pendular movements were inhibited by thiamine derivatives with the following order of potency; DCET≥ Scarbobutoxythiamine (CBT) > S-carbethoxythiamine (CET) =B₁-HCI. Inhibitory effect of B₁-HCl on the peristaltic reflex in the guinea-pig isolated intestine was similar to that of hexamethonium, while that of POET was atropine-like. In the guinea-pig isolated intestine, B₁-HCl specifically antagnized to the nicotine contracture but S-CAT did to not only nicotine but also other spasmogens such as acetylcholine, histamine, barium. Anti-barium effects of thiole derivatives (CET, POET) were also observed in the isolated circular muscle strips of dog intestine, but no effects were observed by the administration of thiazole derivatives (B₁-HCl, O-carbethoxythiamine).
These findings suggest that inhibitory effects of B₁-HCI on the gastrointestinal motility were due to the depression of parasympathetic ganglion in the Auerbach's nerve plexus, but those of S-CAT were not so specific as B₁-HCl.
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