The pharmacological actions of 7 pure Saikosaponins (a, b₁, b₂, b₃, b₄, c and d), the components of Saiko, which plays an important role in Oriental medicine, were studied with special attention to the analgesic effect in repeated cold stressed (SART stressed) mice. Single administration of 10 mg/kg of Saikosaponin (SS) in normal mice gave no analgesic effect, but the analgesic effect of b₂ and c was great in SART stressed mice, and some analgesic effect was noted with a, b₁, and b₃ in SART stressed mice. Administration of 5 mg/kg/day of SS for 5 days in SART stressed mice gave an intense analgesic effect with b₂ and c, and similar administration of a, b₁, b₃ and b₄ also gave some analgesic effect. The inhibition of the body weight increase in SART stressed mice was counteracted in a dose-dependent manner by administration of 2.5-10 mg/kg/day of SSb₂ and c for 5 consecutive days, but similar administration of d augmented the inhibition of body weight. The effect of administration of 5 mg/kg/day of SS for 5 days on the decrease of ACh-response in isolated duodenum from SART stressed mice, which were considered to be in partial vagotonia in small intestine, was studied. While c, b₁, b₂, b₃, a and b₄ were inhibitory, d was entirely ineffective. The effect of administration of SS on the increase of the ACh-response in isolated duodenum from mice stressed by restraint and water immersion, which were considered to be in partial sympathicotonia in small intestine, was also studied. An inhibitory effect was seen with d, which had been without effect in the specimen from SART stressed mice, while no effect of b₂, c and a was noted, despite the positive effect in SART stressed mice. Three kinds of SS effects were distinguished, a central stimulating effect, a central inhibitory effect and a negative effect, based on the hypnotic effect on combined use with pentobarbital, result of measurement of motor activities in open field test in normal mice and experiment on electric resistance of the skin by GSR in SART stressed rats. According to the above results, particularly effects on the change of ACh-response in isolated duodenum, a classification of the action of SS was attempted.

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Further study on identification of metabolites of cinepazide, 4-(3, 4, 5-trimethoxycinnamoyl)-1-(1-pyrrolidinyl) carbonylmethylpiperazine, in rats and men was carried out. New metabolites of cinepazide in rat urine were 4-[1-[4-(3, 4, 5-trimethoxycinnamoyl)-piperazinyl] acetamido]-1-butanol (M-II), 4-(3, 4, 5-trimethoxycinnamoyl)-1-[1-(hydroxypyrrolidinyl)] carbonylmethylpiperazine (M-IV) and 4-[1-{4-(3, 4, 5-trimethoxycinnamoyl) piperazinyl} acetamido]-1-butyric acid (M-VI). Structures of two mono-O-demethylated metabolites of cinepazide predicted in the previous paper were assigned as 3-hydroxy-4, 5-dimethoxycinnamoyl and 4-hydroxy-3, 5-dimethoxycinnamoyl compounds (M-III and M-V) by the FT-NMR spectrometry measured in a mixture of CDCl₃-C₆D₆ (1 : 1, v/v) after methylation with dimethylsulfate-d₆. The corresponding pyrrolidone metabolite of cinepazide was undetectable in rat urine. New metabolites of cinepazide in rat feces were found to be 4-(3, 5-dihydroxy-phenethylcarbonyl)-1-(1-pyrrolidinyl) carbonylmethylpiperazine (M-VIII) and 4-(3, 5-dihydroxycinnamoyl)-1-(1-pyrrolidinyl) carbonylmethylpiperazine (M-IX). Metabolitcs of cinepazide in human urine were studied by both methods-high performance liquid chromatography and mass spectrometry with ion cluster technique. Unchanged drug was mainly excreted in the urine, and M-VI was the major urinary metabolite. The existence of M-IV and M-V was suggested by high performance liquid chromatography. The corresponding pyrrolidone was also undetectable in human urine.

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The sulfoxide reduction of sulindac (cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl)-benzylidenyl] indene-3-acetic acid), an anti-inflammatory agent, was demonstrated in vitro by cell-free preparations of guinea pig liver. The sulfoxide reductase activity was located in both fractions of microsomes and 105000×g supernatant. The microsomal reductase was NADPH-or NADH-dependent, and required the factor present in the soluble fraction for its activity. The factor was heat-labile and non-dialyzable. Furthermore, a pattial purification of the microsomal NADPH-cytochrome c reductase resulted in a paralleled increase of the sulfoxide reductase activity. The present observations suggest that the soluble factor described above functions as an electron transfer component coupled with NADPH-cytochrome c reductase.

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The renal accumulation of dibekacin, one of the aminoglycoside antibiotics, was pharmacokinetically analyzed and the mechanism of the renal accumulation of these antibiotics was investigated. The remaining amounts of dibekacin in the kidneys were adequately expressed by the bi-exponential equation. There was no possibility of a covalent bond between dibekacin and the renal tissue components. The renal accumulation of the aminoglycoside antibiotics was explained in terms of the two successive processes, renal tubular reabsorption and electrostatic interaction between these antibiotics and the tissue components. In other words, these antibiotics were reabsorbed at the renal tubules and transported into renal tubular epithelial cells and bound to the tissue components by electrostatic force. The electrostatic interaction also played an important role in increasing the acute toxicities of aminoglycoside antibiotics.

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The effect of age on the development of hyperemotionality including muricide induced by either olfactory bulbectomy or isolated housing was studied in rats. In olfactory bulbectomized groups, 13-week-old rats showed the highest score of emotionality and shortest latency in the onset of hyperemotionality and muricide among any other groups of rats. On the other hand, in the groups subjected to isolation, 4-week-old rats showed a higher score of emotionality than 13-week-old rats. These results suggest that the age of the rat at the beginning of the experiment is quite important in the induction of hyperemotionality following both olfactory bulbectomy and isolated housing.

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The effect of pretreatment with BHT on the binding of ¹⁴C-BHT to lung microsomes was examined in vitro. The amount of radioactivity bound to microsomal macromolecules significantly decreased by pretreatment of rats with BHT. This decrease was accompanied by a decrement in the content of cytochrome P-450 and in BHT oxidase activity. Furthermore, the behaviour of these components was dependent upon the dose of BHT given. On the other hand, these three components were unchanged in phenobarbital-pretreated rats.

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Incubations of 2-hydroxyestradiol (I), 2-hydroxyestradiol 17β-sulfate (II), and 2-hydroxyestradiol 17β-glucuronide (III) with purified rat liver catechol O-methyltransferase were carried out at pH 7.2 in the presence of Mg²⁺ and (³H-Me)-S-adenosyl-L-methionine. The radioactive methylated products, 2-methoxyestradiol (IV) and 2-hydroxyestradiol-3-methyl ether (V), from each substrate were quantificated by reverse isotope dilution method after their complete separation and acetylation. In the experiments of conjugated substrates, II and III, the analyses of the methylated products were done after their hydrolysis of 17β-conjugate groups with acid or β-glucuronidase. The product ratios (2-methoxy/3-methoxy) of substrates I, II, and III, were 1 : 1, 4 : 1, and 4.5 : 1, respectively. These results are suggesting that 17β-conjugate groups of 2-hydroxyestradiol has directive effect on enzymatic O-methylation of estrogen catechols. Further, it is estimated that following process may be present in the estradiol metabolism in rat and/or humans : estradiol→estradiol 17β-conjugates→2-hydroxyestradiol 17β-conjugates→2-methoxyestradiol 17β-conjugates.

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