Characteristics of aggressive behavior induced in rats by olfactory bulbectomy, midbrain raphe lesions, nucleus accumbens septi lesions and an administration of Δ⁹-tetrahydrocannabinol were compared and the effects of various drugs were investigated in details. Defensive aggression of these rats was readily inhibited by neuroleptics and antianxiety drugs, while muricide (mouse-killing behavior) was selectively suppressed by antidepressants, indicating that muricide of the rat would be a good animal model for depressive illness. It was also clarified that the neural mechanism for inducing muricide and the response to antidepressants differed each other depending upon the method of muricide induction. It is suggested that these various types of muricide are useful in evaluating the mechanisms of action of antidepressants.

抄録全体を表示

1-Aryl-2-pyrazolin-5-ones (1-arylpyrazolones) and 3-anilino-1-(2, 4, 6-trichlorophenyl) pyrazolones having nitrogen-containing five or six membered cyclic imido substituent at each 3-position of pyrazolone and aniline moiety were synthesized by the reaction of 3-phenoxycarbonylaminopyrazolones (5) and 3-(3-phenoxycarbonylamino) anilinopyrazolones (6) with amino acid esters. Treatment of 5 and 6 with ethyl glycinates gave 3-(2, 4-dioxoimidazolidin-3-yl) pyrazolones and anilinopyrazolones (3 and 4). When 5 and 6 were treated with ethyl β-alaninates, the products were not perhydropyrimidinediones but substituted ureas (7 and 8). Hydrolysis of the product (7a) derived from 5 and ethyl N-benzyl-β-alaninate gave the corresponding acid (7d). The cyclization of 7d with dicyclohexylcarbodiimide (DCC) furnished 3-(2, 4-dioxoperhydropyrimidin-3-yl) pyrazolone (16). On the other hand, a condensation product (8) obtained by the reaction of 6 with ethyl N-benzyl-β-alaninate was easily cyclized with sodium ethoxide in ethanol to give imido substituted anilinopyrazolone (14).

抄録全体を表示

The ¹³C-nuclear magnetic resonance (¹³C-NMR) spectra of cyclohexyl, d-, and l-menthyl 6'-O-tritylglucopyranosides and their acetyl derivatives, and the ¹H-NMR spectra of d-and l-menthyl 6'-O-tritylglucopyranoside acetates were recorded, and their signals were assigned. The effects of 6'-O-tritylation upon the conformation around the glycosidic linkage and upon the aglycon moiety were examined. It was found that the trityl group on the sugar moiety affected chemical shifts of the anomeric-proton and -carbon, and of the proton on the carbinyl-carbon and the carbinyl-carbon. Furthermore, ¹H-and ¹³C-NMR chemical shifts of substituent groups on the aglycon moiety on 6'-O-tritylation suggested a relative conformation between sugar moiety and aglycon.

抄録全体を表示

For the investigation of biological adverse effects of herbal drugs, toxicological studies were performed on the methanolic extracts from Peony root (syakuyaku), Peach kernel (toonin), Japanese angelica root (tooki) and Cnidium rhizome (senkyuu) in rats and mice. In the single administration study, these extracts were administered orally or intraperitoneally to male Wistar rats and ddY mice at a dose of 6g/kg (peach kernel, 4g/kg), and acute toxic effects of the extracts were investigated. In the repeated administration study, these extracts were orally administered by intubation to male Wistar rats once a day for 21 d at daily doses of 1.5 and 3g/kg (peach kernel, 0.25 and 0.5g/kg). General appearance and body weight of rats were checked daily, and behavioral, hematological, biochemical and pathological examinations were performed. The results obtained are given as follows. 1) Single administration study. Peony root, Japanese angelica and Cnidium rhizome did not show any sign of toxicity in rats and mice by oral administration, whereas these herbal drugs showed some toxic signs and/or lethal effect by intraperitoneal administration. No species difference in the toxic signs was found between rats and mice. Peach kernel showed a marked lethal effect in both of the animal species by oral administration, but not by intraperitoneal administration. The lethal effect is considered to be due to the toxic action of the cyanide produced from amygdalin in the digestive tract of the animals. Peach kernel also induced rearing and fighting behaviors in rats, but not in mice, by intraperitoneal administration. 2) Repeated administration study. Peony root : Body weight gain was suppressed. Macrocytic anemia was observed in hematological examination. The osmotic resistance of the erythrocytes slightly increased. Spleen weight increased, and a dilatation and congestion in the sinusoid of the spleen were evidenced by pathological observation. However, no evidence of hemolytic anemia was obtained in pathological and biochemical examinations in which no abnormal sign of hemosiderin deposition in the liver and the spleen and no increase in total bilirubin level in the serum were found. The activity of glycylprolyl-dipeptidyl aminopeptidase in both of the serum and the liver and the content of cyt. P-450 in the kidney also increased. Peach kernel and Japanese angelica root : The increases in the serum free cholesterol level and the kidney cyt. P-450 content were observed. Cnidium rhizome : Some toxic signs such as piloerection or salivation were observed. The osmotic resistance of the erythrocytes was slightly increased. Liver weight was increased and the induction of drug metabolizing enzyme activities in the liver occurred, though no abnormal change of the liver was evidenced by pathological observation. The increases in the serum free cholesterol level and the kidney cyt. P-450 content were also observed. It is concluded that a toxicological approach is of importance for investigating biological adverse effects of herbal drugs.

抄録全体を表示

Phenytoin (DPH) and its metabolites were examined in rat urine after ¹⁴C-DPH administration. High-performance liquid chromatography (HPLC), using LiChrosorb RP-18 column and acetonitrile-methanol-0.4 mM phosphate buffer (pH 6.0) (17 : 28 : 55, v/v) as a mobile phase, was employed for the examination of the metabolites. The eluate from the column was monitored by ultraviolet (UV) detector (250nm), and the radioactivity was measured for each fraction. Radio-thin-layer chromatography and the reverse dilution analysis technique have been introduced in order to obtain more detailed informations on the metabolites. From the results obtained, the HPLC method shows that DPH metabolites were separated from the urine sample without being interfered with the urine components, when monitored by UV detector. It was found that the rat urine after ¹⁴C-DPH administration contains some DPH metabolites, such as hydroxyphenytoin, diphenylhydantoic acid, diphenylglycine and also some water-soluble unidentified metabolites.

抄録全体を表示

2-Dansylethyl chloroformate hydrochloride (II) was synthesized as a new fluorescent labeling reagent for alcohols for use in high performance liquid chromatography (HPLC). Treatment of 2-dansylethanol (I) with trichloromethyl chloroformate (TCF) in the presence of pyridine gave II in 98% yield. Compound II reacted with alcohols in dichloromethane at room temperature in the presence of pyridine to give the corresponding highly fluorescent 2-dansylethyl carbonate esters (IIIa-i). Cholesterol and cholestanol were labeled by the present method and chromatographed on a reversed-phased HPLC column (mobile phase : acetonitrile-water-tetrahydrofuran) with a fluorophotometric detector. Their carbonate esters were satisfactorily separated by HPLC. The detection limit of cholesterol was 50 pg (S/N=6). The present studies indicate that II is a useful fluorescent reagent for labeling of alcohols.

抄録全体を表示

A method for the labeling of 5-fluorouracil (5-FU) and four pyrimidine nucleosides (uridine, deoxyuridine, fluorodeoxyuridine and thymidine) with 4-bromomethyl-7-methoxycoumarin (Br-Mmc) using 18-crown-6 as a catalyst is described. The fluorescent derivatives are prepared by adding 5.0mg of Br-Mmc, 1.0mg of 18-crown-6 and 25 mg of potassium carbonate to a solution containing 0.5mg of pyrimidine compounds in 20 ml acetone. The mixture is refluxed for 30min at 75°C. The excess Br-Mmc is treated with n-valeric acid after completion of the reaction. High performance liquid chromatographic separation of these fluorescence derivatives have been obtained on a 25cm column packed with octadecylsilica. The amount of the derivatives is linearly related to the amount of the starting 5-FU and pyrimidine compounds and the procedure can therefore be used in the quantitative analysis. The procedure is simple and requires little or no experience in derivatization techniques. The detection limits of 5-FU, uridine, deoxyuridine, fluorodeoxyuridine and thymidine are 2.5 pg, 5.0 pg, 50 pg, 50 pg and 75pg, respectively. The structures of the fluorescence derivatives are also discussed from the results of thin layer chromatography.

抄録全体を表示

Labetalol (LA) is a new kind of antihypertensive agent that consists of two racemic mixtures, LA-1 (R·S+S·R) and LA-2 (R·R+S·S). These racemic mixtures show a difference in their pharmacological activity. We developed the separative determination of LA-1 and LA-2 by gas chromatography in order to clarify the difference in their excretion and metabolism in human subject. LA was heated with n-butylboronic acid in pyridine at 60°C for 2 h and the reaction mixture injected into gas chromatograph (1.5% OV-1, 285°C). LA-2 boronate had a retention time of 4 min and LA-1 boronate of 5 min, and the resolution of these peaks was almost complete. Linear relationship between peak height ration and weight ratio of LA-1 to LA-2 was observed. By this method, urinary excretion of LA-1 and LA-2 was examined after single oral administration of LA·HCl (100mg/body) to three healthy volunteers. Urine was collected for 24h after administration. To the urine sample was added prochlorperazine maleate as an internal standard, and extracted with ethyl acetate before or after treatment with β-glucuronidase. The percentage of the dose (50 mg as each racemic mixture) excreted as LA-1, its phenolic glucuronide, LA-2 and its phenolic glucuronide were in the range of 1.2-2.4, 11.2-24.6, 0.6-1.3 and 4.7-11.2, respectively.

抄録全体を表示

The present study was carried out to elucidate the effect of Cardamon seed and its active principles in view of cholagogue. The cholagogue effect was observed in acetone extract of Cardamon seed and terpineol. Terpinyl-acetate also possessed cholagogue property.

抄録全体を表示

Enzyme activities and ultrastructural changes in the small intestinal mucosa of thyroxinetreated rats were investigated. Wistar male rats (8 weeks) were treated with thyroxine 3.0mg/kg/d i.p. for 5 or 10d. Other rats were treated with thyroxine for 10d, followed by taking rest for 10 d. Activities of maltase, alkaline phosphatase, Na⁺-K⁺-adenosine triphosphatase (Na⁺-K⁺-ATPase), rotenone insensitive nicotineamide adenine dinucleotidecytochrome c reductase, succinate cytochrome c reductase, nicotineamide adenine dinucleotide phosphate-cytochrome c reductase (NADPH-cyt. c red.) increased in the thyroxine treated rats. On the contrary, the activities of lactase, sucrase, β-glucuronidase, glucose-6-phosphatase (G-6-Pase), β-naphthyl acetate esterase and aspirin esterase decreased in the thyroxine treated rats. Effects on these enzymes by thyroxine were more marked in the 5 d-treated rats than in the 10 d-treated rats except Na⁺-K⁺-ATPase, and were the same to control in the 10 d-treated and 10 d-rested rats except NADPH-cytochrome c reductase and G-6-Pase. Microvilli of small intestinal epithelium were thick and low, and mitochondria, gER, Golgi apparatuses and free ribosomes of the epithelial cells increased in the thyroxine treated rats. Therefore it is suggested that thyroxine affects the absorption of drugs.

抄録全体を表示

tert-Butyl esters of various carboxylic acids were conveniently prepared by applications of a modified Taschner's procedure in which carboxylic acids were treated in a mixture of tert-butyl acetate (1 vol) and tert-butanol (1 vol) with sulfuric acid at 0°C to room temperature.

抄録全体を表示

New flavones, 5, 6, 7, 3', 4', 5'-hexamethoxy, 3', 4'-methylenedioxy-5, 6, 7, 5'-tetramethoxy, and 3', 4'-methylenedioxy-5, 7, 5'-trimethoxyflavone isolated from Bauhinia championii, were synthesized to confirm their structures. These synthesized flavones were identified with the natural fiavones by the physical and spectral data. A new preparation of 3, 4-methylenedioxy-5-methoxybenzaldehyde was also discussed.

抄録全体を表示

Twenty three compounds were isolated from pericarps of peanuts, Arachis hypogaea L., the structures of seventeen constituents among them were determined as follows ; β-sitosterol (I), behenic acid (II), palmitic acid (III), stearic acid (IV), myristic acid (V), lignoceric acid (VI), dancosterin (VII), luteolin (VII), vanillic acid (IX), 5, 7-dihydroxychromone (X), pratensein (XI), chrysoeriol (XII), eriodictyol (XIII), apigenin (XIV), D-glucose (XVIII), soyasaponin I (XIX), and potassium nitrate (XXIII). From leaves of this plant, ferulic acid (XXIV), p-coumaric acid (XXV), aesculetin (XXVI), caffeic acid (XXVII), pinitol (XXVIII), isoquercitrin (XXIX) were isolated in addition to XIX, XXI, XXIII, and their structures confirmed.

抄録全体を表示

The experimental conditions to measure accurately the changes of dermal blood flow (DBF) in rats were studied according to the thermoelectrical element method, which was uninterfered with muscle blood flow and arteriovenous shunt in the precapillary regions. Main factors affecting the stability and the sensitivity to drugs of DBF were the body weight and the treatment to immerse into the water bath. The most suitable conditions were as follows. 1. The body weight was 245-257g. 2. The anesthetized rats were immersed into the water bath at 15°C to the depth of xiphoid process for 10 min. Under these conditions, the changes of DBF by the application of the reference drugs (norepinephrine, dl-α-tocopheryl nicotinate, inositol hexanicotinate, isoxsuprine hydrochloride) were measured accurately.

抄録全体を表示