The interactions between amine local anesthetic dibucaine and pig erythrocyte membranes have been studied by proton and phosphorus-31 nuclear magnetic resonance (1^H-and <31>^P-NMR) spectroscopy. It was found that dibucaine, bound to the membranes, increases the mobility of the hydrophobic acyl chains of the phospholipids, but that it decreases the mobility and/or changes the structure of the polar headgroups. The interactions with peripheral membrane proteins, i.e., spectrin and actin, were found to be weak. These observations indicate that the dibucaine locates across the polar and hydrophobic areas of the lipid phase of the membranes by both electrostatic and hydrophobic interactions. It is assumed that the changes in the mobility and/or the conformation of the phospholipids residing around the Na channel protein are essential in causing anesthesia.

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The structure of gymnemagenin (3β, 16β, 21β, 22α, 23, 28-hexahydroxy-olean-12-ene), the sapogenin of the antisweet principles of Gymnema sylvestre, was established by X-ray analysis of the 3β, 23;21β, 22α-di-O-isopropylidene derivative. On the basis of this result, the structure of deacylgymnemic acid was elucidated as the 3-O-β-glucuronide from the carbon-13 nuclear magnetic resonance spectra.Five antisweet principles, gymnemic acid-III, -IV, -V, -VIII, and -IX, were isolated in pure states from the hot water extract of leaves of Gymnema sylvestre. Of these, three (GA-III, -IV, and -V) were known, while two (GA-VIII and -IX) were new compounds. The structures of GA-VIII and -IX were elucidated as 3'-O-β-D-arabino-2-hexulopyranosyl gymnemic acid-III and -IV, respectively.

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Electrochemical oxidation of methyl (±)-4, 7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3-b]pyridine-5-carboxylate (1), a new dihydropyridine calcium blocker, in both methanol and acetonitrile was investigated by cyclic voltammetry, macroscale controlled potential electrolysis (CPE), in situ electron spin resonance (ESR) and ultraviolet-visible spectral studies. CPE of 1 in methanol at the potential of the first anodic peak on cyclic voltammetry gave four final products, the corresponding pyridine (2, yield, 73.9%), the 2-methoxy-substituted derivative of 2 (3, 11.9%), the 2, 2'-dimer (4, 7.9%) and the 2, 5'-dimer (5, 5.8%), while in acetonitrile, CPE of 1 gave 2 (12.2%), 4 (85.3%) and 5(1.2%). It is suggested that the initial step is a one-electron oxidation of 1 to give the radical cations based on the results of in situ ESR. A possible mechanism of the electrode reactions of 1, which involves one-electron oxidation followed by deprotonation, radical coupling, substitution and further oxidation, is proposed.

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Continuing chemical examination of black tea has led to the isolation of three novel fermentation products, theogallinin (1), theaflavonin (10) and desgalloyl theaflavonin (11). The structure of 1 was established on the basis of physico-chemical evidence to be a condensation product linked through pyrogallol-pyrogallol rings in theogallin (2) and (-)-epigallocatechin 3-O-gallate (3), while 10 and 11 were characterized as B, B'-linked bisflavonoids formed by an oxidative coupling of isomyricitrin (12) and tea catechins [3 and (-)-epigallocatechin (4)]. Furthermore, high performance liquid chromatography analyses of the changes of tea polyphenols during fermentation have revealed that original tea catechins are more rapidly transformed by endogenous phenol oxidase to theasinensins (e.g.6, 8) and oolongtheanin (13) than the formerly known black tea pigments, theafiavins.

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The four stereoisomers of C-nor emetine Pyman (2) were synthesized and isolated as their hydrobromides (2a-d·2HBr). Reduction of 3, 11b-trans dehydro C-nor emetine Pyman (13a) gave an inseparable mixture of 2a and 2b. They were converted into the corresponding 2-phenoxybenzoyl amides (14a, b), and the 3, 11b-trans C_1'-epimers, 14a and 14b, were chromatographically separated. Similarly, the 3, 11b-cis C_1'-epimers, 14c and 14d, were obtained from cis dehydro C-nor emetine Pyman (13b). The configurations of 14a and 14d were determined by X-ray crystallographic analysis. Reduction of 14a-d with BH₃·SMe₂ complex and hydrogenolysis over Pd-catalyst followed by treatment with HBr-AcOH gave 2a-d·2HBr in good yields.

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Facile synthesis of erythro-L-β-hydroxyglutamic acid and its derivative, (2S, 3S)-3-acetoxypyroglutamate, from L-malimide is described. The Key reaction for the synthesis of 3-oxypyroglutamyl intermediate was the furylation of N-acylaminal acetate using zinc bromide-trimethylchlorosilane as an effective catalyst system. Oxidative cleavage of the furyl substituent afforded the 3-acetoxypyroglutamate, which on hydrolysis gave the title amino acid.

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Six new ether-soluble resin glycosides (jalapin), operculins VI, XI, XII, XIII, XIV and XV, isolated previously from Rhizoma Jalapae Braziliensis (roots of Ipomoea operculata), have been characterized on the bases of chemical and spectral data.

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Heterosigma-glycolipids I (1), II (2), III (3), and IV (4), four new Diacylglyceroglycolipids possessing ω3-polyunsaturated fatty acid residues, were isolated from the cultured raphidophycean dinoflagellate Heterosigma akashiwo.Based on enzymatic partial hydrolysis using lipase and physicochemical evidence. the structures of heterosigma-glycolipids I (1), II (2), III (3), and IV (4) have been determined as (2'S)-2', 3'-di-O-(6, 9, 12, 15-octa-decatetraenoyl)glyceryl β-D-galactopyranoside, (2'S)-2'-O-(6, 9, 12, 15-octadecatetraenoyl)-3'-O-(5, 8, 11, 14, 17-eicosapentaenoyl)glyceryl β-D-galactopyranoside, (2'S)-2'-O-(6, 9, 12, 15-octadecatetraenoyl)-3'-O-(3, 6, 9, 12, 15-octadecapentaenoyl)glyceryl β-D-galactopyranoside, and (2'S)-2'-O-(5, 8, 11, 14, 17-eicosapentaenoyl)-3'-O-(6, 9, 12, 15-octadecatetraenoyl) glyceryl 6-O-(α-D-galactopyranosyl)-β-D-galactopyranoside, respectively.

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N-Acetic acid derivatives of 6-aryl-pyrazolo-triazin-4-ones were synthesized for evaluation as new aldose reductase inhibitors. The intrinsic activity of each compound was assessed by measuring the inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All the prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10^-6M&les;IC₅₀&les;10^-4M). Furthermore, biological activity (log 1/IC₅₀) for most of the data sets could be correlated directly to electronic and steric parameters. Finally, spatial configuration of the most active derivative 6c (IC₅₀=2×10^-6M) was compared with that of tolrestat and with pharmacophor requirements of the aldose reductase inhibitor site using a molecular modeling system.

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A series of N-(4-amino-2-butynyl)acetamides were synthesized and examined for their inhibitory activity on detrusor contraction and mydriatic activity as an index of anticholinergic side effect. Among those compounds synthesized, (+)-2-cyclohexyl-N-(4-dimethylamino-2-butynyl)-2-hydroxy-2-phenylacetamide hydrochloride ((+)-13b·HCl), 2-cyclohexyl-2-hydroxy-N-(4-methylamino-2-butynyl)-2-phenylacetamide hydrochloride (13c·HCl), N-(4-dimethylamino-2-butynyl)-2, 2-diphenyl-2-hydroxyacetamide hydrochloride (14a·HCl), and 2, 2-diphenyl-N-(4-ethylamino-2-butynyl)-2-hydroxyacetamide hydrochloride (14b·HCl) showed equipotent inhibitory activity on detrusor contraction to oxybutynin (1) and less mydriatic activity. Further evaluation of these compounds as an agent for the treatment of overactive detrusor has been examined.

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A series of imidazo[1, 2-a]pyridinylalkylbenzoxazole derivatives was synthesized and tested for histamine H₂-receptor antagonist, gastric antisecretory and antiulcer activities. Some of 2-amino-6-[2-(imidazo[1, 2-a]pyridin-2-yl)ethyl]benzoxazole derivatives were found to have good pharmacological activities. Among them, 2-amino-6-[2-(7-methoxy-3-methylimidazo[1, 2-a]pyridin-2-yl)ethyl]benzoxazole (II-11) and 2-acetamido-6-[2-(7-methylimidazo[1, 2-a]pyridin-2-yl)ethyl]benzoxazole (II-38) showed potent antisecretory and cytoprotective activity. The structure-activity relationships of these compounds are discussed.

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The anti-allergic drugs disodium cromoglycate (DSCG) and tranilast are strong inhibitors of hyaluronidase. In the development of new anti-allergic drugs, we studied the inhibitory effects of some natural products on the activation of hyaluronidase. Among the compounds tested, liquiritigenin, isoliquiritigenin and baicalein showed dose-related inhibitory effects. Anti-allergic activities of these compounds were evident from the facts that they inhibited the histamine release from rat peritoneal exudate cells induced by antigen, compound 48/80 and calcium ionophore A-23187, and from their inhibitory effect on Shultz-Dale reaction using sensitized guinea pig ileum.

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To find a novel α-blocker with high α-blocking selectivity against dopamine D₂-receptor affinity, we performed structural modification of the alkylene chains and the substituents on two benzene rings of 2-alkoxy-5-[(phenoxyalkylamino)alkyl]benzenesulfonamide derivatives. The modification of the alkylene chain between the amino moiety in the center of the molecule and the benzene ring (ring A) was found to be the most significant. 5-[2-[[2-(5-Fluoro-2-methoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide (II-4), which possesses 1-methylethyl as the alkylene chain, exhibited high α-blocking selectivity as well as potent α-blocking activity.

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Novel 4-arylpyrimidine derivatives were synthesized by the oxidation of 4-aryl-1, 4-dyhydropyrimidines, and their effects on anti-anoxic (AA) activity in mice and anti-lipid peroxidation (ALP) activity in rat mitochondria were investigated. Among these compounds, ethyl 6-methyl-2-phenyl-4-(4-pyridyl)-5-pyrimidinecarboxylate (4b) has AA activity (10mg/kg, i.p.) and ethyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (4f) has ALP activity (73% inhibition at 10<-5>g/ml). The latter compound (100mg/kg, i.p.) was also effective on arachidonate-induced cerebral edema in rats with comparable potency to that of vitamin E.

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A novel, highly cardioselective ultra short-acting β-blocker, ONO-1101, has been developed for application in the emergency treatment of tachycardia and better control of heart rate in surgery. This agent is approximately nine times more potent in β-blocking activity in vivo and eight times more cardioselective in vitro than esmolol. This β-blocking drug has a short duration of activity, enabling rapid recovery after cessation of administration if side effects occur. It can be used safely in patients suffering from acute heart disease and represents a major therapeutic advance in the treatment of heart disease.

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A new series of 2-substituted 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chlorobenzamides (4-39) including a few 4-fluorobenzyl analogues were prepared and evaluated for their gastrokinetic activity by determining their effects on the gastric emptying activity of phenol red semisolid meal in rats. The C-2 substituent comprises alkoxy and variously substituted alkoxy groups. Among the derivatives, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-2-(n-butoxy)-5-chlorobenzamide (5), its 4-fluorobenzyl (6), and 3-methyl-2-butenyloxy analogues (22) were superior to cisapride and essentially equipotent to the 2-ethoxy analogue (1b, AS-4370 as its citrate) in gastrokinetic activity. These compounds, like AS-4370, had no dopamine D₂ receptor antagonistic activity.

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Optically active trans-isomers of diltiazem were synthesized and their cardiovascular effects were evaluated in anesthetized dogs and in isolated guinea pig hearts.Both (+)-2 (2R, 3S) and (-)-2 (2S, 3R) were much less active than diltiazem (1, 2D, 3S) with short duration of action. No substantial enantiomeric difference in activity was seen between them. Their Ca-antagonistic activities on Ca²⁺-induced contractions in K⁺ -depolarized canine basilar arteries were also examined.Absolute stereochemistry of (+)-2 was determined to be 2R, 3S by X-ray crystallographic analysis.

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Novel indolo[3, 2-b]quinolines (1b-k), having a nitro, amino, acetamido, methanesulfonamido, or glycosylamino group at the 2, 7, or 8-position, were prepared and their antitumor activities against P388 leukemia in mice were examined. The 7-galactopyranosylamino derivative (1g) showed the most potent activity (optimal dose=25mg/kg, T/C>333%, cure rate 5/6).

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Structural modification of the cardiotonic agent, loprinone (E-1020, 1), suggested by data that it has a less positive chronotropic effect than milrinone (15), led us to find novel bradycardic agents that were structurally different from homoveratry amine derivatives. Alkyl-oxy, -thio, and -amino derivatives at the 2-position of the pyridine ring of 1 produced bradycardic activity without a significant effect on blood pressure and myocardial contractility. Aryloxy analogues also decreased heart rate, and members with an electron-withdrawing group at the ortho position of the phenyl ring showed higher activity. Replacement of the imidazo[1, 2-a]pyridine with pyridine resulted in diminished activity. The mechanism of bradycardic activity of these compounds seems to be direct action on the sinus node.

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Six analogues of 1α, 25-dihydroxy-22-oxavitamin D₃ (OCT) (2), 26, 27-dimethyl OCT (5), 26, 27-diethyl OCT (6), 24-norOCT (7), 24-homoOCT (8), 24-dihomoOCT (9), and 24-trihomoOCT (10) were synthesized from the 20(S)-alcohol (11) as the common starting material. In the activity inducing differentiation of human myeloid leukemia cells (HL-60) into macrophages, 26, 27-dimethyl OCT (5) and 24-homoOCT (8) showed the highest activities. The binding properties of these analogues to the chick embryonic intestinal 1α, 25-dihydroxyvitamin D₃ (1) receptor are also described.

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Contractile activity of porcine neuromedin U-25 (p-NMU-25) and various neuromedin U (NMU) peptide fragment amides was examined on chicken crop smooth muscle preparation. The relative activity (expressed as RA value) of p-NMU-25 to porcine neuromedin U-8 (p-NMU-8) was 5.51±0.09, and p-NMU-25 (15-25) was the most potent fragment with an RA value of 7.78±0.05. All C-terminal 11-peptide amides of rat, rabbit and frog NMU peptides retained activity about three-fold higher than the corresponding C-terminal 8-peptide amides. The peptide segment Asn¹⁵-Arg-Arg¹⁷ of p-NMU-25, as well as the corresponding positions of various NMU peptides : Ser¹³-Gly-Gly¹⁵ of rat NMU and Ser¹⁵-Arg-Gly¹⁷ of rabbit and frog NMUs, appeared to be involved in the structural requirements for increased contractile activity in the assay system.

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Twenty compounds were isolated from the roots of Rubia tinctorum which are used as a commercial source of madder color. Among these compounds, mollugin (1), 1-hydroxy-2-methylanthraquinone (2), 2-ethoxymethyl-anthraquinone (11), rubiadin (13), 1, 3-dihydroxyanthraqunone (14), 7-hydroxy-2-methylanthraquinone (16), lucidin (17), 1-methoxymethylanthraquinone (18) and lucidin-3-O-primeveroside (19) showed mutagenicity with Salmonella typhimurium TA 100 and/or TA 98. Since the muntagenic compounds isolated are anthraquinone derivatives with the exception of compound 1, structure-mutagenicity relationships of the anthraquinones were also studied. The results suggested that the greatest activity is exhibited by 1, 3-dihydroxyanthraquinones possessing methyl or hydroxylmethyl group on carbon 2.

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From the stems of Kadsura heteroclita, two new lignans named heteroclitins F and G were isolated and their structures were determined by various spectroscopic means including an X-ray diffraction method. Dibenzocyclo-octadiene type lignans and related compounds isolated from the stems of K. heteroclita, potently inhibited the lipid peroxidation in the rat liver homogenate stimulated by Fe²⁺-ascorbic acid, CCl₄-reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine 5'-diphosphate-NADPH.

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A gas chromatography-selected ion monitoring procedure with chemical ionization is described for the determination of bromovalerylurea (BVU) in human plasma. BVU was extracted with ether after addition of 2-bromo-2-methylpropylurea as an internal standard. The lower limit of BVD quantification by this method was 2ng/0.1ml plasma volume. This procedure was used to determine the sequential plasma levels of BVU in a human volunteer following a single oral dose of a commercial analgesic.

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22-Oxacalcitriol 3-hemiglutarate, a haptenic derivative of 22-oxacalcitriol, was synthesized to obtain a specific antibody for use in radioimmunoassay. Three antisera were elicited in rabbits against the hapten conjugated with bovine serum albumin, and their specificity was examined by cross-reaction study. One of the antisera was found to be satisfactorily specific, and expected to provide a radioimmunoassay useful for the pharmacokinetic study of 22-oxacalcitriol.

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Micrococcus luteun (M. lysodeikticus) labeled with Remazol brilliant blue R (blue ML) was prepared as a novel substrate for the colorimetric assay of lysozyme. The treatment of the labeled substrate with lysozyme resulted in the release of soluble blue products which can be easily measured spectrophotometrically at 600nm. The blue color was most efficiently released at pH 7 and ionic strength of 0.2 on incubation with hen lysozyme at 40°C. A new colorimetric method for the assay of lysozyme using this substrate was developed. The assay system gave a linear dose-response curve, and as little as 0.1μg of human lysozyme (1μg/ml, 100μl) can be detected. The present method is more convenient and reproducible than the conventional lysozyme assay with bacterial cells. Application of the system to the determination of lysozyme in human serum is described.

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Comparative studies were carried out on the interaction of Rhizopus delemar C-lipase with 1, 1, 1-trichloro-2, 2-bis(4-chlorophenyl)ethane (DDT), 2, 2-bis(4-chlorophenyl)ethane (DIM), dichlorobenzophenone (DCBP) and aldrin by means of 2-hydroxy-5-nitrobenzylation of tryptophan (Trp) residues on the 1 : 1, 2 : 1 and 9 : 1 (7 : 1 with aldrin) pesticide-lipase complexes.2-Hydroxy-5-nitrobenzylation was carried out under three conditions : modification with a water-soluble modification reagent, with the same reagent in the presence of olive oil emulsion and with a fat-soluble modification reagent in the presence of emulsion. The Trp residues involved in ligand-binding were specified in tems of their modification patterns.Modification revealed that the binding of pesticide involves five exposed Trp residues. The modification patterns are distinctly different depending on the sort of pesticide. This is consistent with the previous observation that the binding of the above four pesticides affects the binding properties of the lipase quite differently depending on the sort of pesticide. It is suggested for DDT, DIM and DCBP that the binding of the first pesticide molecule, which governs the ensuing complex formation, involves the same Trp residue. This would indicate the presence of three overlapping binding sites for each of three pesticides. On the other hand, firstly binding two aldrin molecules bind to a region not involving a Trp residue.

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Solubilization of limulus test reactive materials from Candida was examined in the presence or absence of phagocytic cells. Solubilized limulus test reactive materials (LTRM) were detected in culture supernatant, and hot water and sodium hydroxide extracts of the acetone dried cells of Candida parapsilosis. Suspensions of Candida cells also reacted with limulus test, and LTRM were released from the acetone dried cells by serum treatment. After treatment of the acetone dried cells with polymorphonuclear leucocytes (PMN) or macrophages (Mφ), a significant amount of LTRM was solubilized. Significant amounts of LTRM were also released by PMN during treatment of live and growing C. parapsilosis. The reactivity of LTRM was completely inhibited by the addition of excess amount of purified (1→3)-β-D-glucan, suggesting LTRM from Candida cells as described above would contain (1→3)-β-D-glucan. These results suggested that LTRM during fungal infection would come from the extracellular water soluble polysaccharide fraction as well as the insoluble cell wall fraction solubilized by the action of phagocytes.

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An antibacterial factor, dolabellanin A, was purified from the albumen gland of a sea hare, Dolabella auricularia. Purified dolabellanin A was a glycoprotein of 250 kilodaltons consisting of 4 subunits, and showed both antibacterial and antineoplastic activities. The two activities were lost in parallel on heating and at low and high pH. This factor was half-maximally active for gram-positive and -negative bacteria at 0.018-0.48μg/ml, and its action was not bactericidal but bacteriostatic. Dolabellanin A did not induce morphological elongation of bacteria or the release of adenosine triphosphate, but it completely inhibited the syntheses of deoxyribonucleic acid (DNA) and ribonucleic acid by E. coli within 6 min. These results suggest that dolabellanin A, which is found in a marine invertebrate, the sea hare, is a new antibacterial protein, and that it exerts its action by inhibiting nucleic acid synthesis, as does a DNA-inhibiting chemotherapeutic drug.

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In the extruding granulation process, granules are prepared by moistening blended powders, sucrose and lactose, and passing the resultant mass through a screen. Many factors affect the properties of granules in this process. The properties of the granulating fluid play an important role, especially when a water/organic solvent system is employed.In this study, a water/isopropyl alcohol system was chosen and the effects of surface tension, viscosity, and the solubility of sucrose and lactose on the properties of the kneading mass and the granules were examined. Deformation behavior and cohesiveness of the kneading mass were influenced by liquid saturation and surface tension. No remarkable variation was observed in mean granule diameter, except in a pure isopropyl alcohol system. Granule hardness increased with the tensile strength of the kneading mass and the amounts of sucrose and lactose deposited; solubility was a dominant factor.

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Viscous ethyl oleate (VEO) was prepared as an oily drug carrier by the addition of alminum stearate or ethyl cellulose. Since the rate of shear of VEO containing aluminum stearate was greatly and nonlinearly changed against the shearing stress compared to that containing ethyl cellulose, the latter was used for subsequent microvascular and organ distribution experiments in rats and hamsters. For infusion into the carotid artery in hamsters, neat ethyl oleate (EO, 4cP) or VEOs of various apparent viscosities (40, 80, 120cP-VEOs) embolized the vascular system in the cheek pouch, although arrival time to the site where the embolization was observed and the embolization period differed depending on the type of oily drug carrier. For infusion into the hepatic artery in rats, however, only 120cP-VEO embolized the vascular system in the liver. After infusion of the oily drug carrier containing 3^H-oleic acid into the artery of hamster cheek pouch and rat liver, 30-50% of the radioactivity was gradually eliminated within 48h, whereas about 80% of the dose was rapidly eliminated after infusion to rat stomach and kidney. In addition, the amount of 120cP-VEO remaining in each organ 48h after infusion was higher than those of EO and 40 and 80cP-VEOs. Histological observation after infusion in rat liver revealed that 120cP-VEO slowly migrated from the artery or arteriole to the sinusoidal capillary region. These results suggest that 120cP-VEO can be used as a drug carrier because of its function of vascular embolization and high retention in a targeted tissue.

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Thermodynamic parameters have been evaluated for the binding interaction between human serum albumin (HSA) and unbranched fatty acids (FFA) on the basis of a flow microcalorimetric measurement at pH 7.4 and 37°C by computer-fitting to single- and two-class binding models. The heat of binding increased exothermically with increasing alkyl chain length. FFA with nine or less carbons bound to only one class of binding sites (n=2) with a binding constant (K) of 10⁴M^-1. FFA with ten or more carbons bound to the first class of binding sites with high affinity K in the order of 10⁵ to 10⁶M^-1, and to the second class with a lower affinity and high capacity. The free energy change of first class of binding sites (ΔG₁) became more negative as the chain length of FFA was increased. The enthalpy change per mol of FFA (ΔH) decreased at the rate of -7.47kJ·mol^-1·CH₂^-1 to a minimum at C9 and then increased due to the hydrophobicity of alkyl chains. Compensation analysis for the i th class of HSA molecule by plotting molar changes of enthalpy (ΔH_mi) against entropy (ΔS_mi) and free energy (ΔG_mi) indicates two distinct binding sites. The first class (i=1) of the long-chain FFA on HSA is an entropy-driven reaction associated with nearly constant values of ΔH_m1 (-43.0±4.8kJ·mol^-1), slightly negative values of ΔS_m1 (-47.4≤ΔS_m1≤-8.1J·mol^-1·K^-1) and -ΔG_m1 values, increasing with increasing alkyl chain length. The second class (i=2) of the long-chain FFA may lie in the same region as the binding sites of the short- and medium-chain FFA with a linear relationship between ΔH_mi-ΔS_mi.

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The effects of dipotassium glycyrrhizinate (GLYK) on the dissolution behavior and bioavailability of amphotericin B(AMB) were investigated. The mixtures of AMB and GLYK were prepared at different molar ratios by lyophilization. Lyophilization resulted in amorphous AMB either alone or in the mixuture. Dissolution rates of AMB of the mixutures were markedly faster than that of lyophilized AMB alone, which was followed by a decrease of dissolution. The initially-enhanced dissolution rate was likely to be due to the improvement of surface wettability of drug particles with GLYK rather than the amorphous state of AMB. A phase solubility study of AMB with GLYK indicated that the increasing solubility was caused by micellar solubilization. The in vitro release rate of AMB from suppositories containing the lyophilized mixtures was significantly accelerated by increasing the amount of GLYK.The rectal absorption of AMB from suppositories containing either the drug alone, a physical mixture or a lyophilized mixture was studied using rabbits. The absorption of the mixuture (AMB/GLYK=1/9) was about 35 times greater in the area under the serum concentration-time curve (0-24h) than that of lyophilized AMB alone. These results suggest that GLYK is useful for improving the dissolution property of AMB and the bioavailability of the drug incorporated in suppositories.

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A simple and quantitative evaluation method for particle size distribution (f_x(r)) of slightly water-soluble drugs dispersed in an aqueous medium together with other water-insoluble additives was developed using a laser diffraction method.The particle size distribution function of the powder mixture, (f(r)), was assumed as f(r)=φ_x·f_x(r)+φ_a·f_a(r), where φis the volume fraction of each component dispersed in a measurement medium and f_a(r) is the distribution function of another water-insoluble additive "a".In order to calculate f_x(r) from f(r), it is necessary to know the density of drug and additive in the measurement medium, d_x and d_a, but this is difficult to determine since particles usually swell in the medium. Thus, a method was developed to use their relative value δ_a (=d_a/d_x).As a practical application, oxolinic acids (OA) of three sizes (OA-S (about 2μm), OA-M (about 7μm) and OA-L (about 24μm)) were used as model drugs. δ_a values were determined for various additives using the mixture of OA-S and each additive. Then, using δ_as, f_x(r) of OA-M or OA-L in the mixture containing OA-M or OA-L and additives was calculated from the f(r)experimentally determined for the mixture. They agreed well with their original distributions.The method was applied to some dosage forms, and the results obtained had good correlation with those from turbidity, wet sieving or dissolution test.

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The permeability of liposome entrapping insulin through the nasal mucosa of rabbit has been studied and compared with the permeability of insulin solution with or without pretreatment by sodium glycocholate (GC). Insulin entrapped in liposome was not detected in the receiver cell using the diffusion cells with the nasal mucosa. On the other hand, permeability of insulin entrapped in liposome increased after the pretreatment of GC. The phospholipids which result from liposomes, were not observed in the receiver. Also, the GC remaining in the nasal mucosa was measured.Considering the mechanism of permeation of insulin entrapped in liposome through the nasal mucosa, the GC remaining in the nasal mucosa may cause the lysis of liposomes.

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Three different crystallization methods, i.e., the solvent change (SC) method, neutralization (NT) method and quasi-emulsion solvent diffusion (QESD) method, were employed to prepare agglomerated tolbutamide crystals (referred to as SC-A, SC-B, NT and QESD). Each of the agglomerated crystals or unagglomerated tolbutamide crystals (abbreviated as bulk) alone (single formulation), magnesium stearate (MgSt; a lubricant)-added single formulation sample (formulation A), and Kollidon CL (a disintegrating agent)-added formulation A samples (formulation B) were compacted into tablets by the direct tableting method. With the objective of elucidating the compressibility of these samples, the following parameters were analyzed : (1) the course of change in the powder bed volume as a function of the applied compression pressure, (2) the pressure-transmission ratio from the upper punch to the lower punch, (3) the course of decompression (ejection force) and (4) the tensile strength of the tablets determined by the diametric compression method. The results of each sample were compared.For each of the single-formulations, formulation A and formulation B, Kawakita's equation was able to be applied to each stage of the compaction process over the tested compression pressure range of 50-1500kg/cm². The limiting value of the compaction ratio of the samples was higher in the order of SC-B>NT>SC-A>QESD>bulk, and each agglomerate showed much higher compressibility than the bulk. Although the agglomerates and bulk showed the same pressure-transmission ratio from the upper punch to the lower punch, the bulk showed a smaller ejection force during decompression. The agglomerates, whose primary crystal diameter is small, showed much larger tensile strength of the compacted tablet than the bulk. The addition of MgSt improved the compaction process, but it weakened the tensile strength of the compacted tablets, especially in the case of the bulk. The addition of Kollidon CL decreased the ejection force due to a decrease in the adhesion force of the tablet to the surface of the die wall. Because Kollidon CL suppressed the effect of MgSt, the tensile strength of the compacted tablets was increased.The above results revealed that the compressibility of the agglomerates, especially SC-B and NT, is much superior to that of the bulk, and that these agglomerates have the properties necessary for direct tableting. Moreover, formulation B was suggested to be useful as a practical formulation for direct tableting.

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The process of the flocculation of monodispersed particles, whose binding strength is assumed to be very strong, had been simulated using the two-dimensional geometrical random coalescence model. The flocculation kinetics and the change mechanism of aggregate shapes were studied. In this simulation procedure, the kinetics were explained to follow a second-order rate equation in agreement with von Smoluchowski's flocculation theory. The morphological parameters, the porosity and the particle diameter of aggregates were indicated to be affected by the number of monodispersed particles and the collision probability, but they converged on one curve under the conditon of normalized flocculation time (t/t_1/2). It was suggested that the change of the aggregate shapes and their enlargement were controlled by the same process, irrespective of the trial conditions. The shape of the aggregate obtained by the flocculation of agglomerated stearyl alcohol beads on the surface of water was similar to that of the simulation. Hence, it was considered that the strength of binding between beads is comparatively strong.

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To improve the instability of prostaglandin E₁ (PGE₁) in ointments, potential use of O-carboxymethyl-O-ethyl-β-cyclodextrin (CME-β-CyD) was examined, comparing with parent β-CyD. Inclusion complexation of PGE₁ in aqueous solution and in solid state was investigated by circular dichroism and carbon-13 nuclear magnetic resonance spectroscopies, kinetic method, powder X-ray diffractometry and thermal analysis. The inclusion ability of CME-β-CyD against PGE₁ was much higher than that of β-CyD, i.e., stability constants determined by the kinetic method were 880 and 290M^-1 for the CME-β-CyD and β-CyD and β-CyD complexes, respectively.The chemical instability of PGE₁ in fatty alcohol propylene glycol (FAPG) ointment and in aqueous solution was significantly improved by the complexation with CME-β-CyD, while parent β-CyD accelerated the degradation in neutral and alkailine solutions. The stabilizing effect of CME-β-CyD seemed to come from 1) the adjustment of microscopic and/or macroscopic pH to about 4 where PGE₁ was most stable, 2) the low hygroscopicity of CME-β-CyD preventing access of water molecules to PGE₁ and 3) the inclusion of the reactive site, where the first effect contributed most significantly to the stabilization. The in vitro release of PGE₁ from FAPG ointments was enhanvced by complexastioin with CME-β-CyD, and its superior release characteristics were retained even after aging. The limited data obtained here suggest that CME-β-CyD is useful for improvements of not only the chemical instability of PGE₁ in ointments as well as solution, but also the releaese rate from the ointment.

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In our previous paper, the utility of the solid dispersion for the control of medicine release was studied and the solid dispersion was prepared by the evaporation of ethanol after dissolving a water soluble medicine (oxprenolol hydrochloride), soluble hydroxypropyl cellulose and insoluble ethylcellulose into ethanol. In this paper, the tableting of the above mentioned solid dispersion granule and mechanism of medicine release from this solid dispersion granule were studied. Microcrystalline cellulose was used as the excipient in this tableting. The disintegration time, crushing strength and porosity were measured for the obtained tablets. The pore size distribution in the solid dispersion granules was measured before and after the dissolution test with a mercury porosimeter to clarify the mechanism of medicine release from the granules. The state of medicine in the granules was analyzed by infrared spectrometry, thermal analysis and X-ray diffractometry.As a result, it was clarified that oxprenolol hydrochloride in ethylcellulose was released from the granules by diffusing and dissolving into the medium in the channels formed by the dissolving of hydroxypropyl cellulose and oxprenolol hydrochloride, as inferred in the previous paper. Furthermore, the compression pressure and pH scarcely affected the dissolution behavior of oxprenolol hydrochloride from the granules. It was thought that the homogeneity of the content of oxprenolol hydrochloride in the granules was very high, and the dissolution rate from the granules could be controlled by the particle size of the granules and the composition ratio of ethylcellulose and hydroxypropyl cellulose in the granules. These results suggest the solid dispersion granule and the tablet prepared with this granule are useful for the sustained release granule and tablet.

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The decomposition products and mutagenic activity in Salmonella typhimurium strains TA98, TA100 and TA104 in the presence and absence of S9 mix of linear dodecylbenzenesulfonate (DBS) in aqueous solution after ozone treatment alone or simultaneous treatment with ozone and ultraviolet (UV) irradiation (ozone/UV treatment) were investigated. The decomposed DBS solutions after these treatments for 4h were mutagenic for strains TA98, TA100 and TA104 both with and without S9 mix, but this mutagenicity disappeared rapidly during further ozone/UV treatment. Mutagenicity of the decomposed solution of DBS, however, was not substantially decreased by treatment with ozone alone. Formaldehyde and glyoxal were identified as the decomposition products of DBS in water by high-performance liquid chromatography after treatment with 2, 4-dinitrophenylhydrazine. Although these two compounds were mutagenic for strain TA104 both with and without S9 mix, they disappeared after further ozone/UV treatment but not after ozone treatment alone.These results indicate that ozone/UV treatment is an effective procedure for purifying drinking water.

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The heats of dissolution (ΔH_d) of fatty acids (FA)-nicotinamide (NAA) complexes, (FA)₆(NAA)₆, were measured at 310.15K in ethanol using a calorimetric technique, where the FA were tetradecanoic acid (C14), pentadecanoic acid (C15), hexadecanoic acid (C16), heptadecanoic acid (C17) and octadecanoic acid (C18). The values of ΔH_d were 527.9, 574.6, 592.7, 640.1 and 656.6kJ mol^-1 for (C14)₆(NAA)₆, (C15)₆(NAA)₆, (C16)₆(NAA)₆, (C17)₆(NAA)₆ and (C18)₆(NAA)₆, respectively. The values of ΔH_d of (FA)₆(NAA)₆ increased by increasing the carbon numbers (n) of the constituent FA. However, the plots of ΔH_d of (FA)₆(NAA)₆ against n showed a zig-zag pattern with an upward convex at an old-numbered position. This is the same tendency as observed for FA-thiamine disulfide (TDS) complexes, (FA)₆(TDS).The differences between ΔH_d of (FA)₆(NAA)₆ and ΔH_d of (6FA+6NAA) were 30-48kJ mol^-1 for even-numbered FA and 45-53kJ mol^-1 for odd-numbered FA, indicating a stronger binding force for (FA)₆(NAA)₆ formed with odd-numbered FA than that formed with even-numbered FA. Furthermore, the estimated values of the binding force between FA and NAA are very small, leading to the conclusion that (FA)₆(NAA)₆ is an inclusion compound or a clathrate formed by van der Waals forces and hydrophobic interactions between FA and NAA.

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The reaction of dihydroxo(1R, 2R-cyclohexanediamine)platinum(II) with (-)-quinic acid gave a water soluble complex, (-)-quinato(1R, 2R-cyclohexanediamine)platinum(II). The crystal structure of the complex was determined by X-ray analysis. The data indicate a chelation of the α-hydroxycarboxylic acid part of quinic acid to platinum(II).The complex shows moderate antitumor activity against murine leukemia L1210 at high doses (T/C×100=179% at a dose of 200mg/kg).

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3-Methyl-1, 8-dihydrocycloheptapyrazol-8-ones (2a-c), prepared from 3-acetyltropolones (1a-c), were treated with diazomethane, methyl iodide, dimethyl sulfate, and diethyl sulfate to give 1- and 2-alkylated compounds. The 1, 8-dihydrocycloheptapyrazol-8-one (2a) also reacted with 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 3-(dimethylamino)propyl, and 2, 3-dihydroxypropyl chloride to afford the corresponding 1-substituted products. A preliminary study was made of the biological activities of some of the obtained compounds.

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(Z)-N-[5-(3-Aryl)-[1, 2, 4]oxadiazoly]-N-[(methylcarbamoyl)methyl]benzamidoximes (3) were synthesized through the reaction of 3-methylglycociamidine (2) with primary nitroalkanes (1) and acetyl chloride. The structural determination of 3 by single crystal X-ray analysis is reported.

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The crystal structure of the isoquinoline : picric acid complex (C₉H₇N·C₆H₃N₃O₇) was determined by means of X-ray crystal analysis. A proton of the hydroxyl group of picric acid was transferred to the nitrogen atom of the isoquinoline molecule in the complex. Isoquinoline and picric acid molecules are arranged alternately along the b-axis, making their molecular planes parallel to each other in the crystal. They overlap each other, and isoquinoline picrate is formed through both ionic interaction and π-bonding.

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Conjugate addition of cyclohexanone lithium enolate to 2-nitro-2-butene and the Nef reaction on the resulting nitronate gave 2-(2-oxopropyl)cyclohexanone in good yield. Treatment of the 2-(2-oxopropyl)cyclohexanone thus obtained with potassium phosphate tribasic (K₃PO₄) in isopropanol gave 2, 3, 4, 5, 6, 7-hexahydro-3-methyl-3aH-inden-2-one (8). Application of the procedure to 1, 3-dimethyl-4-piperidone (11) gave the 1, 3, 4, 6, 7, 7a-hexahydro-6-oxo-2, 4, 7-trimethyl-2H-2-pyrindine (12). Epimerization of 12 with basic alumina gave (±)-tecomanine (1). The short synthesis of the alkaloid demonstrates the usefulness of K₃PO₄ as a base for cyclopentenone annulation of 1, 4-diketones without migration of the double bond.

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Two simple macrolides, patulolides A and C, were synthesized from vitamin C as a chiral starting material.

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All possible diastereoisomers of the dicarboxylic acid (10a), the biologically active form of imidapril (1), were synthesized, and their inhibitory activity against angiotensin converting enzyme (ACE) was examined. The in vitro ACE inhibitory activity of these compounds greatly depended on the configurations of the three asymmetric carbons in each molecule. The (S, S, S) isomer (10a) showed much more potent activity than the others.

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The structure of a 1 : 1 inclusion complex of β-cyclodextrin (β-CD) and a new orally active cephalosporin, pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3(Z)-(4-methylthiazol-5-yl)vinyl-3-cephem-4-carboxylate (ME1207), was estimated by nuclear magnetic resonance (NMR) analysis. The experimental results indicated that the tert-butyl moiety of ME1207 was selectively inserted into the β-CD cavity.

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4-(2-Phthalimidyl)benzoyl cyanide (Phibyl-CN) was designed as a fluorescent labeling reagent for primary and secondary alcohols in high-performance liquid chromatography. Reaction conditions were optimized with hexanol, benzylalcohol, cyclopentanol and 1-phenyl-1-propanol as model compounds of primary and secondary alcohols. Phibyl-CN reacted quantitatively with alcohols on heating at 50°C for 30 min in the presence of 4-dimethylaminopyridine to give the corresponding fluorescent esters which were separated on a reversed-phase column with fluorescence detection. The detection limits for alcohols labeled with the reagent were 0.24-0.38pmol per injection. The extents of conversion of primary and secondary alcohols into fluorescent esters were approximately 100%.

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