We studied the effects of phenothiazine neuroleptics on cell shape and osmotic resistance of human erythrocytes. All of the neuroleptics tested induced cell shape change of the internalization type, due to membrane invagination, and also gave two-phasic effects on the osmotic behaviour of the cells, with a protective effect on hypotonic hemolysis in relatively low concentrations and a stimulative effect in higher concentrations. Both effects were exerted almost immediately upon contact of the cells with the drugs and were dependent on drugconcentrations. The effects on cell shape were independent of temperature while the protective effects on osmotic resistance were slightly temperature-dependent, being weaker at temperatures lower than 37°. Both effects increased in the order of diethazine, promethazine, chlorpromazine, perazine, prochlorperazine and trifluoperazine. A non-phenothiazine drug, amitriptyline, also showed similar effects, in a comparative intensity as diethazine.

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Reactivity of the purine ring to Grignard reagents was examined with 9-phenyl-9H-purine (I) and 7-phenyl-7H-purine (II). Hydrolysis of the additive (s) formed by the reaction of I and the Grignard agent afforded 6-substituted 1, 6-dihydro-9-phenyl-9H-purine (I'). In the case of II, the phenyl group in 7-position produced steric hindrance in this reaction and the alkyl or phenyl group was not introduced into the 6-position, and 8-substituted 8, 9-dihydro-7-phenyl-7H-purine (II') was formed. Oxidation of I'and II'with alkaline ferricyanide respectively afforded 6-substituted 9-phenyl-9H-purine (I") and 8-substituted 7-phenyl-7H-purine (II").

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Microbial transformation of progesterone (I) was attempted by Curvularia lunata IFO (5997). 1-Dehydroprogesterone (IV), androsta-1, 4-diene-3, 17-dione (V), 3-hydroxy-9, 10-seco-1, 3, 5 (10)-androstatriene-9, 17-dione (VIII), 3, 17β-dihydroxy-9, 10-seco-1, 3, 5 (10)-androstatriene-9-one (IX), and 15β-hydroxypregna-1, 4-diene-3, 20-dione (VI) were isolated and characterized.

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We developed an ion-selective electrode with a membrane of a polyvinyl chloride (PVC) matrix responsive to clobutinol (CBu : 1-p-chlorophenyl-2, 3-dimethyl-4-dimethylamino-2-butanol). The PVC matrix membrane was prepared as follows : PVC-tetrahydrofuran solution (PVC content : 14.25%), CBu.-tetraphenylborate salt and dioctylphthalate were mixed in a weight ratio of 14 : 1 : 2. The mixture was spread on a glass plate and left for over 48 hours in order to evaporate the solvent. A 5-10 mm diameter membrane was affixed to a PVC tube (ID : 6 mm, OD : 12 mm). The following electrochemical cell was assembled to examine the response of the membrane electrode. [chemical formula] The CBu. ion-selective electrode exhibited a Nernstian response to the CBu. ion from 10^-1.5 to 10^-4.5M. The membrane potential of the electrode was independent of pH from 3.0 to 8.0. Sodium, potassium, ammonium, and calcium ion inferference was extremely small in the determination of CBu. with this electrode. Ephedrine, methylephedrine, caffeine, antipyrine etc. usually contained in common drugs did not interfere at pH 5 to 7, whereas chlorpheniramine, diphenhydramine and tripelenamine ions interfered. The newly developed PVC membrane electrode is useful as an indicator electrode not only for direct potentiometry of CBu. but also for the precipitation titration with sodium tetraphenylborate.

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Twenty nine new compounds belonging to N-alkyl-3, 5-disubstituted pethidine derivatives were synthesized to investigate the relation between chemical structures and pharmacological activities. Analgesic activity of these compounds was examined by inhibitory action on writhing syndrome produced by 0.6% acetic acid in mice. In general, almost all the compounds, after administration of 50 mg/kg, were proved to have inhibitory action of more than 50 percent ; several of them (No. 11, 16, 26, 28, 29), had complete inhibitory action.

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Acid-catalysed cyclisation of N-substituted mandelohydrazides (II) and X with paraformaldehyde gave hexahydro-1, 2, 4, 5-tetrazine derivatives. Furthermore, the acetyl group on the nitrogen rearranged to alcoholic oxygen during the cyclisation of X so as to give VI.

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Acebutolol hydrochloride was proved by thermal analysis (DTA and TG), IR spectra, and X-ray powder diffraction to have three crystalline forms (form I, II, and III) and an amorphous form. The amorphous form, which was stored at 20°under 91% R.H., was first transformed to forms II and III, and then it was finally transformed to form I. During this transformation, the incorporation and release of water were examined. Form I was stable at this condition, while form II was transformed to form I for 48 hr, and form III was transformed to form I for 2 hr. Further, it was found that the amorphous form was transformed to form II at 80°under 50% R.H. for 3 hr, but at 80°under vacuum it was transformed to form III. Form I at 138°for 8 hr and form III at 130°for 4 hr were transformed to form II. From these results it was concluded that form I was the most stable form at room temperature.

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Lidocaine and its two metabolites, monoethylglycinexylidide and glycinexylidide, were synthesized and their pK_a values determined. Temperature markedly affected pK_a values. Colorimetric determination of these compounds was studied and a flow chart for determination is shown. Hydrolysis percentages in solution as a function of time were checked at various pH and temperatures. The result showed that lidocaine was stable at all pH regions, and monoethylglycinexylidide and glycinexylidide were hydrolyzed to some extent in acid and alkaline conditions. The phenomena of ortho and steric effects were applied to elucidate the above results. It may be considered from the present in vitro experiments that monoethylglycinexylidide is a major intermediate for hydrolysis to xylidine from lidocaine in vivo.

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In order to find new antimicrobial agents, a number of substituted 1, 8-naphthyridine derivatives and related compounds were synthesized. Nitration of nalidixic acid with fuming sulfuric acid and fuming nitric acid gave 1-ethyl-1, 4-dihydro-3-nitro-4-oxo-1, 8-naphthyridine-7-carboxylic acid (30). Ethyl 7-substituted amino-1-ethyl-1, 4-dihydro-6-nitro-4-oxo-1, 8-naphthyridine-3-carboxylate (10b-d, g, h and m) obtained in this work showed nearly the same activity with metronidazole against Trichomonas vaginalis.

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Various labelled compounds shown in Table I-III were fed to the aerial parts of Swertia japonica which contains four 6-C-glucosylflavones, isovitexin (1), swertisin (2), isoorientin (3) and swertiajaponin (4). Naringenin-3-¹⁴C was incorporated not only into 1 and 2 but also 3 and 4, whereas apigenin-4-¹⁴C was almost not incorporated into 1 and 2. In contrast, hemiphloin-3', 5'-T₂ was incorporated into 1 and 2, but not into 3 and 4. Furthermore, caffeic acid and eriodictyol were found to be as good precursors as naringenin for 3 and 4. Isovitexin-and isoorientin-¹⁴C were incorporated into 2 and 4 respectively, but isovitexin-¹⁴C was not incorporated into 3. These results revealed that C-glucosylflavones were biosynthesized via C-glucosylflavanone and that 3'-hydroxylation of 3 and 4 occurs at the stage of naringenin prior to C-glucosylation and the 3'-hydroxyl group also can be introduced at that of p-coumaric acid. 7-O-Methylation of 2 and 4 was confirmed to take place at the last stage of their biosynthesis. C-Glucosylation of flavone was briefly discussed.

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In the course of purification of secretin from porcine duodenum, we also found a fraction containing VIP (vasoactive intestinal polypeptide)-like peptide. This peptide was isolated by various chromatographical techniques and it was identified as VIP by several chemical and biological criteria. Some comparative studies on the typical biological activities among VIP, secretin and glucagon were done. VIP had strong hypotensive activity on rats in the threshold dose of 38 ng/kg. On the other hand, secretin and glucagon showed no effect even in a high dose of 5 μg/kg. VIP had a very weak activity on rat pancreatic secretion in comparison with secretin, and glucagon had no effect. VIP and glucagon had no potentiating or inhibiting effects on rat pancreatic secretion stimulated by secretin. Hyperglycemic effects of VIP on urethane-anesthetized rats were nearly equivalent to those of glucagon, whereas secretin had no effect on blood glucose. While secretin exerted no influence on isolated guinea pigileum, VIP had a dose-dependent contractile activity and glucagon had a weak contractile activity. VIP and secretin intensively relaxed rat fundus strip in a dose of 1 ng/ml with similar potencies. VIP also relaxed guinea pig tracheal chain in a dose of 20 ng/ml, but secretin and glucagon had no effects.

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The theories of drug release from the pinhole of sphere (System-1) and drug release from the slot of sectoral wedge (System-2) are presented and drug release from System-1 was measured, using a sulfamethxazol (SMX) sphere coated with beeswax. The simulation technique for System-1, using a digital computer can be applied to the dissolution of SMX, the amount of SMX dissolved was calculated step by step on the basis of the Nernst-Brunner's dissolution model, and a good agreement was found between the calculated and measured amount of SMX. The simulation technique for System-2 can be applied to Brooke-Washkuhn experiments and a good agreement was found between the calculated and measured amount of stearic acid from System-2. The proposed theories and simulation techniques are applicable to various drug delivery systems with various geometry and are useful for the selection of the ideal form.

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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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A sensitive and specific method for the determination of phylloquinone (PK) and menaquinone-4 (MK-4) in biological materials was developed. PK and MK-4 extracted from biological materials were separated by high performance liquid chromatography using Nucleosil[○!R] C₁₈ column with ethanol-water as a mobile phase. The separated PK and MK-4 were detected by fluorometry after reaction with ethanolic sodium borohydride in a reaction coil (0.8 mm i.d. ×100 cm) connected on-line to a chromatographic column. This method was applied to the determination of a very small quantity of PK or MK-4 in plasma and liver. Minimum detectable quantity of PK or MK-4 was 0.4 ng (about 1 pmol) and the coefficient of variation was about 2.0%. The proposed method is simpler, more specific and sensitive than other conventional methods.

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Heating of 6-(methylsulfonyl)-9-phenyl-9H-purine (1) with dilute sulfuric acid or acetic acid results in its decomposition into 9-phenyl-9H-purin-6-ol (II). The methylsulfonyl group in I easily undergoes nucleophilic substitution with hydroxide, methoxide, phenoxide, aniline, 2-furfurylamine, and hydrazine to respectively form II₁, 6-methoxy-(II₂), 6-phenoxy-(II₃), 6-anilino (III₁), 6-(2-furfurylamino)-(III₂), and 6-hydrazino-9-phenyl-9H-purine (III₃). I also reacts with pyrrole in the presence of sodium amide to form 6-(1-pyrrolyl)-9-phenyl-9H-purine (III₄). I also reacts with malononitrile, ethyl cyanoacetate, phenylacetonitrile, acetylacetone, and acetophenone in dimethyl sulfoxide, in the presence of potassium hydroxide, to respectively afford 9-phenyl-9H-purine-6-malononitrile (IV₁), ethyl α-cyano-9-phenyl-9H-purine-6-acetate (IV₂), α, 9-diphenyl-9H-purine-6-acetonitrile (IV₃), 3-(9-phenyl-9H-purin-6-yl)-2, 4-pentanedione (IV₄), and 2-(9-phenyl-9H-purin-6-yl) acetophenone (IV₅). This reaction can be utilized for introduction of a carbon chain into the 6-position of the purine ring.

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Reaction of 6-chloro-9-phenyl-9H-purine (I) with malononitrile (II₁), ethyl cyanoacetate (II₂), phenylacetonitrile (II₃), acetylacetone (II₄), or acetophenone (II₅) in dimethyl sulfoxide, in the presence of potassium hydroxide, under stirring at 90-100°for 1 hr respectively affords 9-phenyl-9H-purine-6-malononitrile (III₁) (74%), ethyl α-cyano-9-phenyl-9H-purin-6-acetate (III₂) (79%), α, 9-diphenyl-9H-purine-6-acetonitrile (III₃) (77%), 3-(9-phenyl-9H-purin-6-yl)-2, 4-pentanedione (III₄) (9%), and 2-(9-phenyl-9H-purin-6-yl) acetophenone (III₅) (5%). This reaction can be utilized for the introduction of a carbon chain into the 6-position of the purine ring.

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The methyl group in 8-methyl-9-phenyl-9H-purine (I) and 8-methyl-7-phenyl-7H-purine (II) undergoes condensation with aromatic aldehydes (III) to give 8-(2-arylethenyl)-9-phenyl-9H-purine (IV) and 8-(2-arylethylenyl)-7-phenyl-7H-purine (V). In general, better result was obtained by refluxing in methanol, in the presence of sodium methoxide (B method), than by heating in the presence of acetic anhydride at 190-200°(A method).

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The selenium dehydrogenation of guaiene gave guaiazulene (7-isopropyl-1, 4-dimethylazulene), isoguaiazulene (7-isopropyl-2, 4-dimethylazulene) and three by-products, which were detected and separated by gas chromatography. The two by-products were respectively confirmed as 7-isopropyl-1, 2, 4-trimethylazulene and 7-isopropyl-1, 4, 8-trimethylazulene from elementaly analysis and nuclear magnetic resonanse and mass spectra.

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A series of 4, 5-dihydro-2, 6-disubstituted-3 (2H)-pyridazinones (V) were synthesized and evaluated for pharmacological activity. Some of these compounds (V-d, h, i, m, p and q) were found to have mild diuretic activity, however, no compound revealed hypotensive activity in normotensive rats.

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The critical micelle concentration (cmc) of sodium cholate in aqueous solution was determined by the iodine method. The apparent value of cmc was affected by the concentration of iodine added. In order to determine the corrected value of cmc, it is therefore necessary to extrapolate of the iodine concent ration to zero. The corrected cmc value by this method was in good agreement with the cmc values in the literature determined by various other methods. Since the physiological activities of bile salts were considered to be greatly influenced by the environment of the gastrointestinal tract, the effect of pH and ionic strength on the cmc value of sodium cholate was examined. The value of cmc decreased with lowering pH and with increasing ionic strength.

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