The behavior of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) at the interface between the solution and a gold electrode has been studied by specular reflectivity measurement and cyclic voltammetry in 0.05 M carbonate buffer (pH 10.0). Current-potential (i-E) curves obtained for FMN and FAD showed redox peaks at about -0.5 V (vs. Ag/AgCl), suggesting that the isoalloxazine moieties of these compounds participate in the electron transport. The reflectivity-potential curves for these compounds measured simultaneously with the i-E curves showed a marked decrease in reflectivity in the potential region more positive than about -0.8 V. Such a trend suggests that adsorption of these compounds, as well as of their reduction products, takes place on the electrode surface. In order to obtain information about the adsorbed states of these molecules, the data were analyzed according to the theoretical treatment of McIntyre and Aspnes. The results suggest that both FMN and FAD are adsorbed with their isoalloxazine rings in contact with the electrode surface. In addition, the adenine moiety of FAD appears to come partly into contact with the surface. The reduced forms of FMN and FAD are also observed to lie in essentially the same states as their oxidized forms.

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Hydroxyapatite (HAP) in water exhibited a buffer function in the region from weakly acidic through weakly alkaline pH. Equilibrium pH depends on the amount of HAP added, and on the species and concentration of added electrolyte. This function seems to originate from the ability of HAP to adsorb OH-and/or from the protonation-deprotonation equilibrium of surface phosphate ion. Theoretical calculation of the suspension pH was attempted. The isotherm of OH- adsorption from aqueous solutions of NaOH mixed with NaCl was of Langmuir type. The saturated amount of OH- adsorption was almost constant irrespective of the amount of NaCl added, but the binding constant increased with the amount of added NaCl. The adsorption isotherms, however, formed just one curve irrespective of the amount of NaCl added when they were expressed as a function of the thermodynamic activity of NaOH. On the other hand, the amount of adsorbed OH- increased with the amount of Ca²⁺ added, because Ca²⁺ is adsorbed on the HAP surface and forms a positively charged adsorption site for OH-. An electrophoresis experiment confirmed that HAP particles have positive charges due to adsorbed Ca²⁺ even in solutio at high pH.

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A new compound, pyracrenic acid (1), was isolated from the bark of Pyracantha crenulata ROEM. of Rosaceae by tracing its granulation-suppressive activity by the fertile egg method in the course of an extensive search among crude drugs and plants for anti-inflammatory constituents. Methylation of 1 with diazomethane-ether solution gave methyl O, O-dimethylpyracrenate (6), which was cleaved by hydrolysis into methyl betulinate (7) and O, O-dimethylcaffeic acid (8). Thus, 1 has the structure of 3β-(3, 4-dihydroxycinnamoyl) oxylup-20 (29)-en-28-oic acid. Results obtained by the cotton pellet method showed that 1 potently inhibits the formation of granulation tissue.

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Treatment of quinoline 1-oxide (1a) with α, α'-azobisisobutyronitrile (AIBN) ordimethyl α, α'-azobisisobutyrate in boiling benzene for 5 h affords 2-(1-cyano-1-methylethyl) quinoline (2a) or 2-(1-methoxycarbonyl-1-methylethyl) quinoline (4) in 31.9 or 24.9% yield, respectively, accompanied with a small amount of quinoline in each case. The 1-oxides of lepidine, 3, 2'-diquinolyl and 4-nitroquinoline (1c, 1d and 1e), and isoquinoline 2-oxide (6) similarly react with AIBN to produce the corresponding α-substituted products (2c, 2d, 2e and 7). The reaction of pyridine 1-oxide (8) gives not only the 2-substituted pyridine (9 : 1.5%) but also the 4-substituted one (10 : 3.0%). On the other hand, the reactions of 1a and 6 with phenylazotriphenylmethane in boiling benzene afford the α-phenyl N-oxides (12 : 17.2% and 14 : 34.5%) and their deoxygenated products (13 : 3.5% and 15 : 2.9%).

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5-(Substituted-thiomethyl)-6-carbamoyluracils (IIIa-f and VIa-c) were prepared in two steps from 5-chloromethyl-6-ethoxycarbonyluracil (I). Oxidation of IIIa-c gave the corresponding sulfones (IVa-c). The compounds thus prepared were examined for growth inhibition of L-1210 cells in vitro and some of them exhibited high activity.

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Treatment of β-cellobiose with 2 molar equivalents of trityl chloride in pyridine at 100°C for 1 h afforded three unusual ditritylates (2, 4, and 5) as well as the 6, 6'-ditritylate (3) which was the expected product. The ratios of 2, 4, and 5 to 3 were approximately 2, 2, and 1 : 60, respectively. Each unusual ditritylate was isolated by column chromatography and was crystallized as needles. Their structures were established by the use of ¹H nuclear magnetic resonance (NMR), ¹³C-NMR, optical activity measurements, etc. It was concluded that 2 is trityl 6'-O-trityl-β-cellobioside, 4 is 2, 6'-di-O-tritylcellobiose, and 5 is trityl 6-O-trityl-β-cellobioside.

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The reaction of C₂-substituted 1, 2, 3, 4-tetrahydroquinazolin-4-ones (1) with acetic anhydride and pyridine was carried out in order to elucidate the effect of the C₂-substituent. It was found that the various types of reactions occurred depending on the kind and number of C₂-substituents of 1, 2, 3, 4-tetrahydroquinazolin-4-ones (1).

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The reaction of 2-substituted 1-methyl-1, 2, 3, 4-tetrahydroquinazolin-4-ones (THQ) with acetic anhydride afforded two types of products depending on the number of C₂-substituents. The reaction of 2-monosubstituted 1-methyl-THQ (6) gave the corresponding N₃-acetyl-THQ derivatives (7), while the reaction of 2, 2-disubstituted 1-methyl-THQ (8) afforded rearranged products, 2, 3-disubstituted 1-methyl-1, 4-dihydroquinolin-4-ones (9). A mechanism is proposed for the reaction of 8 to give 9.

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A series of 1, 3-diphenyl-1-butanone derivatives (11-14) was synthesized as part of a search for new psychotropic agents. In the reaction of 4-chloro-1, 3-diphenyl-1-butanones (8a, d) with piperidine derivatives (10, 15), rearranged products (16-18) were obtained together with 1, 3-diphenyl-1-butanone derivatives (11, 14, 20). A reaction mechanism involving the cyclization of 8a, d to cyclopropane derivatives (22a, d) and subsequent addition reaction with piperidine derivatives (10, 15) to 22a, d is proposed.

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Various 4-indolediazonium salts were prepared for the first time by the diazotization of 4-aminoindole derivatives. They underwent various reactions parallel to those of general arene diazonium salts, and were found to be suitable intermediates for the preparation of substituted indoles carrying a hydroxy, halogeno, or cyano group at the 4-position. Attempts to introduce various carbon side chains into the 4-iodoindole derivatives gave satisfactory results and a key intermediate, 4-(3-hydroxy) 3-methyl-1-buten-1-yl) indole, for the synthesis of (±)-6, 7-secoagroclavine was also prepared.

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The synthesis of optically active "1-thiathienamycin"13a and other (hydroxyethyl)-penemcarboxylic acids from the 8R and 8S azetidinones 3 and 4 via an intramolecular Wittig reaction of the trithiocarbonatephosphoranes 7 is described. Trans and cis penem esters 8 and 9 were found to form an equilibrium mixture on heating. The antibacterial activities of these penemcarboxylic acids are discussed.

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Irradiation of the 2-methylpyridine N-acylimides (12b-d and 17a-c) condensed with a thiophene, furan, or pyrrole ring on the b-side of the pyridine ring gave the corresponding fused 1H-1, 2-(13b-d and 18a-c) and 3H-1, 3-diazepines (14b-d and 19a-c), together with the parent fused pyridines (10 and 15a-c), whereas the N-unsubstituted N-imide (12a) gave only the 1H-1, 2-diazepine (13a) and no 1, 3-diazepine. In this ring-expansion reaction, the initial photo-induced rearrengement may take place on either side of the pyridine nitrogen to give two kinds of diaziridine intermediates (21) and (22) ; the former may give 1, 2-diazepines directly, whereas the latter may further rearrange to the aziridine intermediate (23), followed by ring-expansion to give the 1, 3-diazepines. Some reactions of the new diazepines thus obtained were also examined.

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A series of 5-fluoro-6-substituted-5, 6-dihydrouracil-5-carboxylic esters (13), -5-carboxamides (15, 16), and -5-carbonitriles (18, 19) was prepared by direct fluorination of the corresponding uracil-5-carboxylic esters (6), -5-carboxamide (14), and -5-carbonitrile (17) with fluorine or trifluoromethyl hypofluorite (CF₃OF) in the presence of water, methanol and/or acetic acid. Hydrolysis of the above-mentioned products under mild conditions gave 5-fluorouracil (1a) in high yield. Some applications of the present method for the synthesis of 1-(2-tetrahydrofuryl)-5-fluorouracil (1b) were also described.

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A new and simple procedure has been developed for the synthesis of 2'-amino-2'-deoxyguanosine (9) and -adenosine (15) and related compounds. An enzymatic transaminoribosylation between 2-chlorohypoxanthine (6) and 2'-amino-2'-deoxyuridine (4) afforded 9-(2-amino-2-deoxy-β-D-ribofuranosyl)-2-chlorohypoxanthine (8), which was chemically converted to 9 and its derivatives. 2'-Amino-2'-deoxyinosine (7) enzymatically prepared was also subjected to synthetic processes to give 15 and its derivative. The combination of chemical and enzymatic reactions was found to be useful for the synthesis of some sugar-modified purine nucleosides.

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O-(α-D-Glucopyranosyl)-(1→6)-O-β-D-glucopyranosyl-(1→6)-N-(L-β-aspartyl)-α-D-glucopyranosylamine has been prepared, as a model of a derivative possibly present in the glomerular basement membrane of rats, by condensation of the corresponding trisaccharide α-amine with α-ethyl benzyloxycarbonyl-L-aspartate in the presence of diethylphosphorocyanidate. This was followed by hydrogenolysis, de-O-acetylation, and deethoxylation of the resulting trisaccharide-amino acid linked derivative to remove the protecting groups. The ¹³C-nuclear magnetic resonance spectra of this product and related glycosylamine derivatives are analyzed and discussed.

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Acetylation of the C-6 hydroxyl group in oridonin (1), which is difficult by the use of acetic anhydride in pyridine, was investigated using acetic anhydride in the presence of some Lewis acids. A reagent system of acetic anhydride in the presence of a catalytic amount of boron trifluoride etherate was shown to be effective for this purpose. This reagent system was shown to be useful for selective acetylation of the alcoholic group (s) in compounds which have both alcoholic and phenolic hydroxyl groups.

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14-O-Acyl derivatives of oridonin were prepared and tested for antitumor activity against Ehrlich ascites carcinoma cells in the mouse. In a series of derivatives 7-12, the activity increased with increase of the acyl carbon chain length. The 14-O-benzoyl derivative 5 was shown to have the same order of activity as oridonin. 6-O-Acyl derivatives were also prepared and tested. In a series of derivatives 13-15, no activity was observed at the doses of 5 mg/kg and 10 mg/kg in mice, at which doses oridonin did exhibit activity. Thus, the importance of the ester side chain and the hydrogen-bonding for antitumor activity was demonstrated in oridonin and its derivatives.

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Ring transformations and ring expansions of ka-acetyl-5a, 6a-dihydro-6a-ethoxy-carbonyl-6H-cyclopropa [e] pyrazolo [1, 5a] pyrimidines (3, 4 and 5) are described. For example, treatment of 4a with potassium hydroxide in ethanol gave 4-acetyl-1-(4-cyanopyrazol-3-yl)-5-methylpyrrole-2-carboxylic acid (7a), the structure of which was confirmed by X-ray crystal structure determination. On the other hand, it was found that 3a reacted with ethanol, with ethanol in the presence of potassium hydroxide, or with acetic acid to give 7, 8-dihydro-8-ethoxy (or acetoxy)-4H-pyrazolo [1, 5-a] [1, 3] diazepines (17, 11 or 24, respectively) in moderate yields. Furthermore, when aqueous dioxane was used as the reaction medium, 3a was transformed to ethyl 6-pyrazolo [1, 5-a] pyrimidinepyruvate (22), which was found to exist as a mixture of keto and enol tautomers. The mechanism of formation of these products is discussed.

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A novel one-step and high-yield isoxazole formation of 2-aroylcyclohex-2-enones is described. Treatment of such an enone with hydroxylamine under acidic conditions (NH₂OH·HCl in EtOH) gave the corresponding 3-aryl-6, 7-dihydro [2, 1] benzisoxazole. Changes in the reaction conditions caused marked changes in the course of the reaction. A possible mechanism for these reactions is put forward.

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Preparation and cyclization of 2-benzoyl-3-ethoxycarbonylmethylcyclohex-2-enone and its derivatives have been investigated. Photochemical ring-closure followed by oxidative dehydrogenation was observed in suitably fixed triene derivatives. The results suggest that the cyclization of the photoenols (trienes) of 3-alkyl substituted 2-benzoylcyclohex-2-enones to anthracenone derivatives occurs photochemically.

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A set of 6α- and 6β-(hydroxy, acetoxy, and p-bromobenzoyloxy)-1, 1, 10β-trimethyl-trans-decal-2-ones was synthesized in an unequivocal manner, and the ¹H-nuclear magnetic resonance (NMR) spectra, TH effect (ASIS shift on continuously changing the solvent from chloroform-d to benzene-d₆), and ¹³C-NMR spectra of these compounds are discussed in relation to the conformations of ring A. In solution, ring A of the 6β-derivatives was shown to be more distorted (flattened) than that of 6α-derivatives. This was also true in the crystalline state as determined by X-ray analyses of their p-bromobenzoates. The TH effect was found to reflect sensitively small conformational changes in ring A.

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Although diazomethane is used in the Arndt-Eistert synthesis, it is both highly toxic and also explosive, and hence should be very carefully handled. In place of this hazardous diazomethane, stable and safe trimethylsilyldiazomethane (TMSCHN₂) was found to be very useful for the Arndt-Eistert synthesis. TMSCHN₂ was easily acylated with a carboxylic acid chloride in tetrahydrofuran-acetonitrile, and thermal treatment of the acylated product in benzyl alcohol and 2, 4, 6-trimethylpyridine smoothly gave the benzyl ester of a homologated acid. Nucleophiles other than benzyl alcohol could also be used. TMSCHN₂ may also be able to replace diazomethane in other areas of chemistry.

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A representative mucilage, named Dioscorea-mucilage B, was isolated from the rhizophors of Dioscorea batatas DECAISNE. The final preparation was homogeneous as determined by ultracentrifugal analysis, polyacrylamide gel electrophoresis, and gel chromatography. Its water solution gave the intrinsic viscosity value of 21.0, and its molecular weight was estimated to be about 2000000. It was composed of partially acetylated mannan and of protein containing small amounts of phosphorus in a ratio of approximately 1.0 : 2.2. The polysaccharide moiety was isolated by treatment with Pronase followed by gel chromatography. Its molecular weight was estimated to be about 99000. Methylation and partial acetolysis studies showed that the polysaccharide is mainly composed of β-1→4 linked D-mannopyranose residues having about one fourth degree of branching at the C-3 positions. The O-acetyl groups were located at positions 6 and 2, 3, 6 of some of the mannose units.

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Many kinds of 1-(2-chloroethyl)-3-substituted-3-β-D-glycopyranosyl-1-nitrosoureas (V) were synthesized and tested for antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma. The reaction of aldohexoses such as D-glucose, D-mannose, and D-galactose with primary amines followed by treatment with 2-chloroethyl isocyanate usually gave a mixture of structural isomers of glycosylureas (III'). Complete isomerization into thermodynamically stable β-D-glycopyranosylureas (III) was observed when the mixture of isomers was dissolved in formic acid. Glycopyranosylureas (III) were nitrosated with 5 equivalents of dinitrogen tetroxide followed by treatment with methanol to give the corresponding nitrosoureas (V) in good yields. Many of the nitrosoureas (V) were remarkably active against both leukemia L1210 and Ehrlich ascites carcinoma and showed greater therapeutic ratios than those of the positive controls, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 3 [(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-(β-D-glucopyranosyl)-1-nitrosourea. In particular, some of the galactopyranosylnitrosoureas showed excellent antitumor activities and sixtyday survivors against leukemia L1210 were observed at dose levels of 25, 50 and 100 mg/kg of the compounds. These nitrosoureas (V) appear to be activated nonenzymatically by attack of the hydroxyl group of the sugar moiety on the carbonyl group to give the cyclic carbamate (VI) without generation of the isocyanate (XI).

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A decanucleotide dC-C-C-T-C-G-A-G-G-G was synthesized by phosphotriester block condensation. Three protected blocks, dCCCTp, dCGAp and dGGG were prepared using N-acyl, 5'-O-monomethoxytrityldeoxynucleosides as the starting materials. The protected dGGG which served as the 3'-terminal block was synthesized by condensation of 3'-O-benzoyl-N-isobutyryldeoxyguanosine (5'-hydroxy component) with 5'-O-monomethoxytrityl-N-isobutyryldeoxyguanosine 3'-O-p-chlorophenyl phosphate (3'-O-phosphodie ster component) using mesitylenesulfonyl triazolide as the condensing reagent followed by removal of the 5'-monomethoxytrityl group for repeated condensation. The other two blocks were prepared by using the 3'-O-p-chlorophenyl phosphoranilidate of N, 5'-protected deoxynucleosides as the 3'-end unit (5'-hydroxy component). The phosphoranilidate of the fully protected trimers was removed by treatment with isoamyl nitrite for the condensation with the 5'-hydroxyl group of the growing chain. Fully protected nucleotides were isolated by chromatography on silica gel and the deblocked product was purified by ionexchange chromatography on DEAE-cellulose. The decanucleotide was characterized by mobility shift analysis and complete enzymatic digestions after labelling the 5'-end with [γ-³²P] ATP using polynucleotide kinase.

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The reaction of N²-isobutyryl-9-(2'-O-trifluoromethanesulfonyl-3', 5'-di-O-tetrahydrofuranyl-β-D-arabinofuranosyl) guanine with tetra-n-butylammonium fluoride or an appropriate metal halide in dimethylformamide aftorded N²-isobutyryl-3', 5'-di-O-tetrahydrofuranyl-2'-halogeno-2'-deoxyguanosines. The deprotection of these products led to 2'-halogeno-2'-deoxyguanosines. The ultraviolet absorption properties, ¹H and ¹³C nuclear magnetic resonance spectral properties of the products were recorded.

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A simple and highly sensitive rate assay of serum γ-glutamyltranspeptidase activity is described, using a novel fluorogenic substrate, 7-(γ-L-glutamyl)-4-methylcoumarinylamide. The reaction is initiated by adding 20 μl of serum, and fluorescence development in 1 min due to the 7-amino-4-methylcoumarin liberated at 37°C is followed directly on a recorder. A close correlation was found between activities measured by the fluorometric method and by a conventional method using a chromogenic substrate, γ-L-glutamyl-p-nitronanilide.

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Pharmacokinetic evaluation of oxacillin in man was carried out by detailed investigation of the urinary excretion profiles of unchanged oxacillin and metabolites. A new metabolite, penicilloic acid of the 5-hydroxymethyl derivative of oxacillin, was discovered in human urine excreted after oral administration of oxacillin. This metabolite was formed by cleavage of the β-lactam ring of the 5-hydroxymethyl derivative (a known active metabolite of oxacillin), not by hydroxylation of the 5-methyl group on the isoxazolyl moiety of penicilloic acid of oxacillin. The time courses of excretion of the new metabolite as well as unchanged oxacillin and known metabolites (penicilloic acid and 5-hydroxymethyl derivative) were measured by HPLC analysis of urine excreted after oral administration of oxacillin tablets to human subjects. The values for cumulative excretion amount at infinite time (X^∞) and mean residence time (MRT) for each species were estimated by moment analysis of excretion rate vs. time curves. The rate constants for absorption, metabolism, and urinary excretion were calculated by non-linear least-squares fittings of the time course data using a one compartment model. The results indicate that the excretion ratio (X^∞/D, D=500 mg) and MRT value as averages of five subjects are 27.4% and 1.76 h for unchanged oxacillin, 16.1% and 3.79 h for penicilloic acid, 22.2% and 2.04 h for 5-hydroxymethyl derivative, and 22.4% and 3.89 h for penicilloic acid of the 5-hydroxymethyl derivative. The conversion ratio at each elimination step and the MRT value intrinsic to each metabolite were evaluated from the results of moments.

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The effects of an antitumor protein P-MSY on the numbers of IgM producing cells and IgG producing cells were investigated. Groups of ICR-SLC newborn mice were injected intraperitoneally with P-MSY in doses of 1 to 10 μg/animal and their immune response was assessed at 21 days of age by measuring the antibody production in response to ovine erythrocytes according to the method of Jerne et al. The group of mice administered P-MSY at a dose of 1 μg/animal showed significant increases of the numbers of both direct PFC (IgM-producing cells) and indirect PFC (IgG-producing cells). The number of direct PFC of the test group on day 4 was 962.0 ± 153.8/10⁶ cells, compared with 453.0±77.16/10⁶ cells of the saline-treated control group. The number of indirect PFC of the test group on day 6 was 479.6±70.52/10⁶ cells compared with 192.8±32.14/10⁶ cells of the control group. Experiments were conducted to assess the effect of P-MSY on the peripheral blood lymphocyte subpopulations (T- and B-cells) in groups of newborn guinea pigs by identification and counting of T- and B-cells according to the microplate assay technique of Wilson et al. Guinea pigs dosed i.p. at the neonatal stage with 10 or 20 μg of P-MSY displayed a significant elevation of the T-cell percentage in peripheral blood with a significant relative decrease in the B-cell subpopulation (p≤0.05).

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α-Fetoprotein (AFP) produced by rat AH-66 hepatoma cells was purified and specific antibody was obtained from the serum of an immunized horse. AFP messenger ribonucleic acid (mRNA) (approximately 2700 nucleotides) was isolated by affinity chromatogrophy with oligo (dT)-cellulose of RNA extracted from AFP-synthesizing polysomes of the hepatoma cells.

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The expression of the gene of α-fetoprotein (AFP) was studied in AH-66 hepatoma cells and adult rat liver cells. With purified AFP mRNA as a template, [³H]-labeled AFP complementary deoxyribonucleic acid (cDNA) (around 1000 nucleotides) was synthesized by the use of reverse transcriptase and was used for assaying the nucleotide sequence involved in AFP gene and in its transcripts by the hybridization technique. Upon treatment with DNase I, the AFP gene in AH-66 nuclei was digested preferentially, whereas that in rat liver nuclei was not. These results show that the AFP gene exists in a relaxed conformation in AH-66 but takes a more condensed structure in rat liver. Micrococcal nuclease selectively cleaved the AFP gene in AH-66, as did DNase I. It also preferentially recognized the AFP gene in rat liver, although to a lesser extent than that in AH-66. Chromosomal proteins extracted from AH-66 and ratliver chromatin were divided into four fractions with QAE-Sephadex A-25 (CP_{0, 0.1, 0.25 and 3} respectively). Liver chromatin was dissociated and reconstituted in the presence of each of AH-66 CP_0-3 and, conversely, AH-66 chromatin was reconstituted in the presence of each of liver CP_0-3. Reconstituted chromatins were transcribed by E. coli RNA polymerase and the transcripts were annealed to AFP cDNA. AH-66 CP_0.1 activated the AFP gene transcription strongly, while none of the liver CP_0-3 inhibited the expression of the gene.

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Two thymopoietin fragments, H-Val-Thr-Leu-Pro-Ala-Gly-Glu-Gln-Arg-Lys-Asp-Val-Tyr-OH (positions 24-36) and H-Glu-Gln-Arg-Lys-Asp-Val-Tyr-OH (positions 30-36), were synthesized using protecting groups removable by hydrogen fluoride treatment. The in vitro additions of these synthetic fragments could restore the low E-rosette forming capacity of cells in a patient with lupus nephritis to normal levels. The in vitro effects of tridecapeptide (positions 24-36) and heptapeptide (positions 30-36) fragments of thymopoietin on the low E-rosette forming capacity of cells in a patient with lupus nephritis were also compared with that of the synthetic pentapeptide fragment (positions 32-36). The relative potency of the heptapeptide was 65.22 and that of the tridecapeptide was 40.54 based on the pentapeptide (100.00) as a standard.

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Rectal absorption of diclofenac (DC) and its salts with sodium (DCNa), L-arginine (DC-Arg), L-lysine (DC-Lys), and L-histidine (DC-His) was studied in dogs, rabbits and rats. Plasma levels of unchanged DC were measured by high performance liquid chromatography. Both the bioavailability and the plasma peak level of DC-Lys were the largest among the salts studied. The bioavailability of DCNa on oral administration in terms of plasma levels of DC was observed to be much larger than after rectal administration of DC but it was of the same order as those of rectal administration of DCNa, DC-Arg, and DC-His. The extents of bioavailabilty in rabbits and in rats were similar, but considerably better than that in dogs. The irritative effects of DC salts on the rectal mucosa in rats were studied by gross and light microscopic examinations following the administration of suspensions in 1% methyl cellulose solution. DC-Arg showed the weakest irritation of the rectal mucosa, and the irritation caused by 20% suspension was equivalent to that of 5% suspension of DCNa. The protective effects of counter ions against the histological damage caused by DC to the rectal mucosa increased in the order or sodium≥lysine≥arginine. From these results, it appears that the basic amino acid salts of DC may be useful as rectal delivery preparations for clinical use.

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The stability of clavulanic acid in aqueous solutions has been investigated over a pH range of 3.15 to 10.10 at 35°C and at an ionic strength of 0.5. The changes in the concentration of intact clavulanic acid in buffer solutions were determined by reversed phase HPLC with UV-detection using a mobile phase containing tetrabutylammonium bromide. The observed degradation rates at various pH's were found to follow pseudo-first-order kinetics, and were significantly affected by catalysis due to buffer salts. The catalytic rate constants were estimated at three different concentrations of buffer systems. The pH vs. rate profiles obtained from non-buffer-catalyzed rate constants, k_pH, revealed that the degradation in alkaline solutions proceeded, as a whole, about 10 times faster than in acidic media, and maximal stability was attained at pH 6.39. The Arrhenius activation energies at pH 3.94, 6.67, and 8.74 were estimated as 19.0, 14.7, and 18.3 kcal/mol, respectively.

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A pharmacokinetic investigation on the urinary excretion of clavulanic acid in man was carried out. Combinations of clavulanic acid (125 mg) and amoxicillin (250 mg) were given orally to human subjects, and the subsequent urinary concentrations of intact clavulanic acid, amoxicillin, and the latter's metabolites (penicilloic acid and penamaldic acid) were determined by the high performance liquid chromatography method. From the urinary excretion rate vs. time curves for each species, the values of cumulative excretion amount at infinite time and of mean residence time were estimated by means of the moment analysis method. The results showed that when clavulanic acid was dosed in combination with amoxicillin, 27 to 45% of the dosed amount of clavulanic acid was excreted in the urine as an intact form with a mean residence time of 1.6 to 2.1 h after administration, while the corresponding values for amoxicillin were 56 to 73% (including metabolites) and 2.0 to 2.6 h (for the intact form). These results indicate that clavulanic acid may undergo less absorption (and/or more extensive metabolism and extra-urinary excretion) and faster urinary excretion than amoxicillin. By comparison of the results with those obtained after individual doses of clavulanic acid and amoxicillin to the same subjects, it was found that there was no appreciable kinetic interaction between clavulanic acid and amoxicillin ascribable to the combined dose, although the analysis of variance indicated that the difference in the excreted amounts of penamaldic acid of amoxicillin between combined and individual doses was significant at the 5% level.

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The inactivation profile of rabbit muscle creatine phosphokinase (CPK) has been investigated in Tris-acetate buffer solutions under various conditions of pH and temperature. The inactivation pattern follows apparent first-order kinetics at pH very close to 6.00 (isoelectric point of CPK) and 30 to 39°C and at pH 7.40, 39°C. The activation energy of the inactivation at pH very close to 6.00 is 31.8 kcal/mol. The inactivation half-lives of CPK are 13.6 h (pH 5.95, 30°C), 7.9 h (pH 5.93, 35°C), 3.0 h (pH 5.90, 39°C) and 11.9 h (pH 7.40, 39°C). At pH 6.70, the inactivation profile follows a biexponential curve at 30°C and at 39°C. The time course consists of two types of inactivation : an initial rapid inactivation (α-phase) and a gradual inactivation (β-phase). Anomalous irregular inactivation profiles are also observed at pH 7.00, 7.40 and 8.00 at 30°C as well as at pH 8.00 at 39°C. Some possible explanations of these irregular inactivation profiles are presented.

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The absorption and distribution of creatinine and urea, which are considered to pass through the water-filled pores of biological membranes easily, were investigated in hereditary muscular dystrophic mice as model animals afflicted with a disease which changes the structure and function of the cell membrane. The V_d'extrap for creatinine was remarkably larger in dystrophic mice than that of the control. Whole-body autoradiograms showed that creatinine was distributed rather more uniformly throughout the body in dystrophic mice than in the control at 2 min. A similar, but less pronounced, tendency was also observed in the case of urea. For both chemicals, the urinary excretion of radioactivity in 24 h following oral administration was significantly larger in dystrophic mice than in the control (p<0.02). The above results indicated that the membrane permeability to these two chemicals was enhanced by the disease.

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The use of DL-polylactic acid (PLA) microspheres as a means to achieve sustained release of butamben, tetracaine, and dibucaine was examined in vitro. As a first step, PLA solutions in an organic solvent containing the drug were dispersed in viscous aqueous solutions, then microspheres were formed by a solvent-evaporation process. The release mechanism was examined by scanning electron microscopy. The effects of polymer solvents and nonsolvents on the microsphere characteristics and release patterns from the microspheres were examined. The effects of drug contents and microsphere size on release patterns were also investigated.

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Bradykinin-related substances were studied in vitro and in vivo for bradykinin-potentiating activity. Of the ten peptides which augmented the contractile response of isolated guinea pig ileum to bradykinin, des-Pro²-bradykinin was the most potent. Its potency was 1.9 times that of potentiator B, a bradykinin potentiating peptide obtained from the venom of Agkistrodon halys blomhoffii. This peptide also potentiated the vasode-pressing activity of bradykinin in rats and inhibited angiotensin converting enzyme. These findings indicate that des-Pro²-bradykinin, like venom peptides, potentiates the activity of bradykinin, possibly by inhibiting angiotensin converting enzyme (kininase II).

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The perpendicularly twisting conformation of an anion radical of 10-(α-(o-tolyl)-benzylidene)-9 (10H)-anthracenone was studied by the use of electron spin resonance (ESR) measurement. By comparison with previous results on 10-diphenylmethylene-9 (10H)-anthracenone and 10 (9-xanthenylidene)-9 (10H)-anthracenone, it was found that this structural feature of the compound was a result of the presence of the carbonyl group. Semi-empirical molecular orbital calculations with an open shell model revealed a correlation between the twisting angle about the central double bond of anion radicals of some thermochromic ethylenes and the π-electronic charge distribution on the double bond, and were found to be in reasonable agreement with the conclusion obtained from ESR measurements. It became apparent that twisting decreased the double bond character of the central double bond. A qualitative interpretation of the distribution of the unpaired electron in the molecule is presented.

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8α, 9α- (IIa) and 8β, 9β-epoxyhexahydrocannabinol (IIIa) were prepared from Δ³-tetrahydrocannabinol (Ia) by three reaction steps. Epoxidation of acetylated Ia with m-chloroperbenzoic acid gave a mixture of 8α, 9α- and 8β, 9β-epoxyacetates. By treatment of the mixture with lithium aluminum hydride, IIa and IIIa were prepared in 27.3 and 18.2% yields, respectively. Mass and proton nuclear magnetic resonance spectra data for IIa and IIIa are also presented.

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A new alkaloid, O-methylmaritidine, from Narcissus tazetta L. (Amaryllidaceae) has been assigned the structure (I) on the basis of the close correspondences of infrared, nuclear magnetic resonance, optical rotatory dispersion, ultra violet, and mass spectra to those of alkaloids of known structures.

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The photochemical behaviour of 9-cis-retro-γ-retinal (II) was investigated by high-performance liquid chromatography. A new isomer, 9, 13-di-cis-retro-γ-retinal (III) was isolated from the irradiation products of II.

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The chiral hydrazone (II), obtained by the condensation of N-aminoephedrine with benzaldehyde, was reacted with Grignard reagent to give the chiral hydrazine (IVa) in almost 100% diastereomeric excess. On the other hand, the chiral hydrazone (III) was reduced by lithium aluminium hydride to give the chiral hydrazine (IV). Hydrogenolysis of the chiral hydrazine (IVa) gave (R)-α-phenylethylamine (Va) with more than 97% optical purity, and l-ephedrine used as a chiral auxiliary reagent was recovered.

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The thermal decarboxylation of some unsaturated acids (1, 5, 6, 8, and 9) incorporated into six-membered lactams was examined. Although 8 and 9 did not undergo decarboxylation when heated neat at 175-180°C and 240-245°C, respectively, for 2 h, 1, 5, and 6 were decarboxylated in 1, 1, 2, 2-tetrachloroethane at 135°C. The relative ease of the reaction was in the order of 1&ge;6»5. In the case of 1, the rate-decreasing effects observed on dilution and on the addition of trichloroacetic acid suggest the reaction to be a dimeric intermolecular process.

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A sensitive method for the assay of histamine N-methyltransferase in rat tissues is described. N^τ-Methylhistamine formed from histamine under the optimum conditions for the enzyme reaction is extracted with chloroform, derivatized to a fluorescent product with the use of o-phthalaldehyde and 2-mercaptoethanol, and determined by high-performance liquid chromatography with fluorescence detection. This method allows the simultaneous determination of histamine and N^τ-methylhistamine. The limit of detection for N^τ-methylhistamine formed is 3.5 pmol per assay. The method is simple and is suitable for the routine assay of histamine N-methyltransferase in sample preparations obtained from tissues.

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A voltammetric detector and a fluorometric detector combined with a high performance liquid chromatograph were applied to the analysis of methoxy derivatives of 3, 4-dihydroxyphenylalanine, and the results obtained were compared with those obtained with a 254 nm ultraviolet detector. Response was linear over a wide range of concentrations and detection was sensitive and selective. The contents of 3-methoxy-4-hydroxyphenylalanine in the plasma of normal persons were measured.

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Cyclo (-Tyr-Arg-) (I) and its three stereoisomers, in which one (or both) of the constitutive amino acids was replaced by the corresponding D-amino acid, were synthesized. Diketopiperazines were prepared from dipeptide methyl esters by the use of acetic acid as a catalyst. When administered intracerebrally into mice, I exhibited more potent analgesia than its three stereoisomers, and its activity was five times more potent than that of H-Tyr-Arg-OH. The positions of the two side chains of diketopiperazines are discussed on the basis of the proton magnetic resonance spectral data.

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Two representative preparations of antitumor lichen-polysaccharides, that is, GE-3, a partially O-acetylated pustulan-type β-D-glucan isolated from Gyrophora esculenta MIYOSHI, and UR-1-1, a lichenan-like β-D-glucan obtained from Usnea rubescens STIRT., were tested to examine their effects of the phagocytic response of the reticuloendothelial system (RES) in mice. The phagocytic activity was evaluated by measuring the vascular clearance of colloidal carbon 24 h after a single intraperitoneal administration of a test sample at a dose of 100, 50, or 25 mg/kg. At the dose of 100 mg/kg, GE-3 exerted a marked RES-stimulating effect, which was comparable with that given by 50 mg/kg of zymosan : the effect appeared to decrease with decreasing dose. On the other hand, UR-1-1 failed to enhance the phagocytic activity at any of the three doses tested. In addition, it appeared that introduction of either O-lauroyl or O-carboxymethyl functions into the GE-3 molecule caused considerable loss of activity.

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Physicochemical properties of some polymorphs of phenobarbital were studied. A new polymorph, form III-Ph, with a slightly changed crystal habit was obtained by addition of phenytoin at the time of recrystallization. The transition temperature and the heat of transition between form III-Ph and form III, and between form III and form II were determined to be 46°C and 0.201 kcal/mol, and 77°C and 0.404 kcal/mol, respectively, by solubility measurement. As the dissolution rates of form III-Ph and form III were higher than that of form II, they are expected to show better bioavailability than form II.

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