The electronic structures of 34 hydroxamic acids [R-(CONHCH₂)_n-CONHOH, R=aromatic or aliphatic, n=1 or 0] were calculated by the INDO method and their urease inhibitory potencies were discussed in terms of the calculated electronic parameters and molar refraction. The charge distribution of-CONHOH residue which has been expected as a functional group for inhibition slightly be affected by the change of R-moiety and by the presence or absence of the-CONHCH₂-residue. The best improved regression equation indicated that the inhibitory potency of hydroxamic acids was parabolically varied with the molar refraction and that the increase of the inhibitory potency by the presence of-CONHCH₂-residue was explained by the variation of the charge density of a carbon atom directlv bonding the-CONHOH group.

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The purpose of this investigation is to elucidate the relationship between the time course of pharmacologic effects and drug disposition after administration of metformin, an oral antidiabetic drug of biguanides. Alloxan diabetic rats and normal rats were used in the experiments. After administration of metformin, plasma glucose levels, blood pyruvate levels, blood lactate levels, plasma pancreatic glucagon immunoreactivity (pancreatic GI) and plasma gut glucagon like immunoreactivity (gut GLI) were determined as well as serum concentrations of metformin. In alloxan diabetic rats, gut GLI levels were significantly correlated to the logarithm of tissue metformin levels, calculated from serum metformin levels. The blood lactate, pyruvate and plasma glucose levels were also linearly related to gut GLI levels, after metformin administration. It was also clarified that metformin did not inhibit the intestinal absorption of glucose and that metformin presumably inhibited the hepatic gluconeogenesis. It is reasonable to consider that the effect of metformin on the gut GLI level is the primal effect, and that other pharmacologic effects such as plasma glucose lowering, blood lactate and pyruvate increasing effects are the consequences of the primal effect, at least in alloxan diabetic rats. While in normal rats, plasma gut GLI levels were not significantly related to metformin tissue levels, however, plasma glucose levels were considerably correlated with the logarithm of the plasma or tissue metformin levels. These results indicated that the effect of gut GLI was entirely masked by endogeneous insulin, which might be secreted by metformin administration.

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Augmentation of the host's immunity by combined in situ freeze-destruction of the tumor (cryosurgery) and administration of the antitumor active protein-bound polysaccharide, EA₆, isolated from a hot water extract of an edible mushroom, Flammulina velutipes (CURT.ex FR.) SING., was investigated in sarcoma 180 bearing ICR mice. Oral administration (p.o.)of the EA₆ stimulated anti-sheep red blood cells (SRBC) IgM antibody-producing activity of the spleen cells, and also delayed hypersensitivity (DTH) against SRBC in swelling of the foot pads of the tumor-bearing hosts. When EA₆ p.o. was combined with cryosurgery, further augmentation of IgM-producing activity and DTH reaction to SRBC was recognized as compared with the EA₆ single use. But the reticuloendothelial system of the mice, estimated by carbon clearance test, was not activated by EA₆ p.o. or combined with cryosurgery.

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The antitumor effect of protein-bound polysaccharide, EA₆, derived from fruit bodies of Flammulina velutipes (CURT.ex FR.) SING., when combined with a vaccine treatment was studied by the challenge test in BDF₁ mice and L1210 murine leukemia system. Intensification of the antitumor effect of EA₆ was dependent on doses, timing, and frequency of intraperitoneal administration of the material to the immunization by concanavalin A and/or glutaraldehyde treated L1210 vaccine. Administration of EA₆ prior to the injection of the vaccine, or repeated injection of more than 4 times did not increase the life span of the animals. But when EA₆ was given (40mg/kg) after the injection of the vaccine, marked prolongation of the life span (ILS of 223%) was observed against challenging of 1×10² cells of L1210. Combined treatment of EA₆ with vaccine exhibited prolonged ILS in the mice challenged with 1×10³ cells of L1210. The specific immunity for L1210 induced by the vaccine was not affected by EA₆.

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The effects of Brij 58 on microsome-mediated benzo[a]pyrene (BP)-metabolism were investigated. At a concentration of 0.01%, which did not decompose the microsomal mixed-function oxidase system, Brij 58 increased UDP-glucuronyl transferase activity on 3-hydroxy-BP to 560% of the control level. Quantitative changes of BP-metabolites by glucuronidation were found by high performance liquid chromatography. On incubation in the presence of UDP-glucuronic acid, the amounts of phenols decreased but the amounts of dihydrodiols did not change. Brij 58 enhanced the decrease in phenol metabolites. Unexpectedly, the binding of BP-metabolites to DNA was found to be higher in the presence of UDP-glucuronic acid, and Brij 58 also enhanced the binding in the presence of UDP-glucuronic acid. The ratio of bound adducts with BP-7, 8-dihydrodiol-9, 10-oxide to those with 9-hydroxy-BP-4, 5-oxide, which were separated by Sephadex LH-20 column chromatography, was increased by UDP-glucuronic acid and further enhanced by Brij 58. These results are discussed in relation to the role of glucuronidation in metabolism of BP.

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The investigation was undertaken to study a possible mechanism for adriamycin cardiotoxicity. The activities of superoxide dismutase and catalase in the heart of mice were increased significantly by the intraperitoneal administration of 15mg/kg of adriamycin. In contrast, these enzymes in the liver and kidney were unaffected by this dose of adriamycin. In vitro studies revealed that adriamycin inhibited the NADH-cytochrome coxidoreductase activity of mitochondria in the guinea pigs heart. Moreover adriamycin stimulated the formation of superoxide anion radical in mitochondria isolated from guinea pigs. Particularly, the formation of superoxide anion radical in the heart mitochondria was 5 times higher than that in the liver mitochondria particle. On the other hand, the contents of superoxide dismutase in the heart were significantly lower than that in the liver. These results suggest that the cardiotoxic effect of adriamycin is caused by the following mechanism : adriamycin directly stimulates the formation of superoxide anion radical, particularly in the heart mitochondria. In spite of the induction of defence enzymes such as superoxide dismutase and catalase, their abilities seem to be swamped by enhanced active oxygen radicals.

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Inclusion complex of prednisolone with β-cyclodextrin (β-CyD) in 1 : 2 molar ratio was prepared and its dissolution, membrane permeation and oral absorption behaviors were examined. The rates of dissolution and permeation through a cellophane membrane in water were significantly increased by β-CyD complexation. A crossover bioavailability study was performed using human subjects with lower doses of prednisolone tablets, where the plasma levels of the drug were determined by radioimmunoassay. The enhanced bioavailability of prednisolone by β-CyD complexation suggested the possibility of smaller doses and fewer side effects in prednisolone therapy.

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The present research is on a milky sap obtained from the Antiaris toxicaria tree (Moraceae) which is called Upas or Ipoh in Indonesia. The crude sap was administered to anesthetized rats, and changes in electrocardiogram (ECG) and systemic blood pressure were observed. Biologically and pharmacologically active components were extracted from the crude sap by means of water-acetone solution. Based on the strength of chemical qualitative detection tests of the sap extract (SE), cardiac glycosides are supposed to be the main components. The SE inhibited the Na⁺-, K⁺-ATPase (EC 3.6.1.3) which was partially purified from guinea pig heart muscle. When the SE and, concurrently, authentic ouabain were applied to isolated frog heart muscles, the fall of twitch tension was observed after the increased tension on mechanograms. These facts suggest that the main components of the milky sap are cardiac glycosides, and the glycosides affect Na⁺-, K⁺-ATPase activity of muscle membrane and heart muscle contraction.

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After the intravenous administration of isoniazid (INH ; 0.37mmol/kg) or hydrazine (Hz ; 0.16mmol/kg), the minor metabolite of INH, γ-aminobutyric acid (GABA) and Hz were measured by means of gas chromatograph-mass spectrometer (GC-MS) using deuterium labeled GABA (d₂-GABA) and nitrogen fifteen labeled Hz (¹5N-Hz) as internal standards. In both cases, we successfully detected Hz and GABA in the brain. The brain GABA elevating effect of Hz was much higher than that of INH in spite of low dose.

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The covalent binding ratio of cephalosporins (CEZ, CER, CET and CTX) to human serum albumin was examined at pH 7 and pH 10. The antibiotic equivalents were larger at pH 10 than at pH 7. The degree in the binding ratio of the 4 cephalosporins was CET>CER>CTX>CEZ at pH 7 and CER>CET>CTX>CEZ at pH 10.

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Effects of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), the synthetic chemotactic peptide, and its analogues on blood pressure were investigated in the rabbit, rat, mouse, dog, cat and guinea pig. The administration of FMLP (5μg/kg i.v.) induced the depressor effect in the rabbit but no effect was observed in the other animal species. The only peptide which showed a similar effect as FMLP was N-formyl-L-methionyl-L-methionyl-L-phenylalanine (FMMP) among the peptides relating to FMLP. Tachyphylaxis was observed in the hypotensive action induced by the two peptides.

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Clomipramine, which is used as antidepressant and possesses calmodulin inhibitory activity, circumvented partly the vincristine resistance in vivo. Although vincristine alone at 30-200μg/kg did not confer a significant therapeutic effect in vincristine resistant P388 leukemia (P388/VCR)-bearing mice, clomipramine at doses of 20 to 50mg/kg administered daily for 10 d with vincristine enhanced the chemotherapeutic effect of vincristine in P388/VCR-bearing mice. Approximately a 30% increase in life span occurred. Although the circumvention of vincristine resistance was not achieved perfectly, it could be speculated that more than 98-99% of vincristine resistant tumor cells which could not be killed by vincristine alone could be killed by this approach.

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Effect of highly purified squalene (HP-SQ) obtained from liver of a shark, Centrophorus atromarginative GARMAN, on antitumor activity and host's immune response was studied in sarcoma 180 bearing female ICR mice. HP-SQ was administered intraperitoneally (i.p.) to solid tumor-bearing or healthy mice at the dose of 0.1ml/mouse/d for consecutive 10d. The administration of HP-SQ exerted the host's resistance against challenging 5×10⁴ cells of ascites sarcoma 180, and it resulted in marked prolongation of survival of the mice (ILS ; 110%). Function of the reticuloendothelial system estimated by a carbon clearance test was enhanced by i.p. administration of HP-SQ in both the healthy and the tumor-bearing mice. Number of IgM antibody forming cells against sheep red blood cells (SRBC) in the spleen was counted 4d after intravenous injection of 2×10⁷ cells of SRBC. The number of the IgM antibody forming cell increased by HP-SQ administration in the tumor-bearing and the healthy mice. Delayed hypersensitivity reaction against SRBC measuring swelling of the foot pads of mice was also stimulated by the i.p. administration of the material.

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