meso-Tetra [2- (8-hydroxyquinolyl)] porphine was synthesized by the Rothemund method as a model of porphyrin with metal chelating groups in the peripheral region. The compound was soluble in dimethylformamide (DMF) but practically insoluble in water. Addition of Cu (II) perchlorate to the DMF solution resulted in biphasic spectral changes, an instantaneous change and a subsequent slow change. The spectrum after the first step showed the formation of the free base porphyrin with metal-chelated 8-quinolinol moieties. The second step was observable in the presence of a large excess of Cu (II) and was ascribed to the formation of the Cu (II) -porphyrin with Cu (II) -chelated 8-quinolinol. Addition of perchloric acid to the solution of the metalloporphyrin gave rise to the spectrum assignable to the Cu (II) -porphyrin with unchelated 8-quinolinol.

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A methanolic solution of 2-methoxy-4-methyl-4-phenyl-2-cyclohexenone (I) was irradiated with a 100 W mercury lamp to give 4-methyl-4-phenyl-2-cyclohexenone (III) and 1-methoxy-5-methyl-6-phenylbicyclo [3.1.0] hexan-2-one (IV). When a benzene solution of I was irradiated, only IV was obtained. On the other hand, 2-methoxy-4-methyl-4-phenyl-2, 5-cyclohexadienone (II) gave 2, 2-dimethoxy-6-methyl-6-phenylbicyclo [3.1.0] hexan-3-one (V) and 6, 6-dimethoxy-5-methyl-5-phenyl-3-cyclohexenone (VI) on photoirradiation in methanol. In benzene, 6-methoxy-6-methyl-5-phenyl-2, 4-cyclohexadienone (XI) was obtained.
Compound II was treated with m-chloroperbenzoic acid in a bilayer system of methylene chloride-aqueous disodium orthophosphate at room temperature to give 5, 6-epoxy-6-methoxy-4-methyl-4-phenyl-2-cyclohexenone (XVI) and its stereoisomer (XVI'). 5, 6-Epoxy-2-methoxy-4-methyl-4-phenyl-2-cyclohexenone (XVIII) was obtained by treatment of II with hydrogen perokide in a basic medium. 2, 3 : 5, 6-Diepoxy-6-methoxy-4-methyl-4-phenyl-6-hexanolide (XVII) rather than the expected diepoxide (XII) was obtained by the alternative oxidation of XVI or XVIII.

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Four geometric isomers of a leukotriene B₃ derivative (1b, 2b, 3b, 4b) and their nor derivatives (1a, 2a, 3a, 4a) were synthesized selectively from a common starting material by the same methodology using the Wittig-Horner reaction. All optical isomers of all-trans nor leukotriene B₃ dimethylamide (1a), one of the eight compounds, were also synthesized.

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It has been found that N- [α- (piperidinocarbonyl) benzylidene] trimethylsilylmethylamine reacts with unsymmetrical dipolarophiles to give 2, 2, 4- or 2, 2, 3-trisubstituted pyrrolidines in the presence of tetrabutylammonium fluoride or trifluoroacetic acid, respectively.

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Nitration of 3-acylindoles in the presence of MeCN solvates of Cu²⁺, Al³⁺, and Fe²⁺ salts yielded 3-nitroindole, 4-nitro-and 6-nitro-3-acylindoles, of which 3-acetyl-4-nitroindole was subsequently transformed into dehydrochuangxinmycin (7), the dehydro derivative of the antibiotic alkaloid chuangxinmycin (2).

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N-Benzyl-1, 4-dihydronicotinamides having 2-methyl, 6-methyl and 2, 6-dimethyl substituents were prepared and their reactivities toward an activated carbonyl compound (hexachloroacetone) were investigated. The reaction rates were especially enhanced for the 2, 6-dimethyl derivative, with the order of the rates being 2, 6-dimethyl>2-methyl>6-methyl. The steric and electronic effects of the methyl group (s) are discussed based on the ultraviolet spectra and redox potential data.

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N- (p-trans-Coumaroyl) -and N- (p-cis-coumaroyl) tyramines (1, 2), lunularic acid (3) and p-coumaric acid (4), which are inhibitors of prostaglandin (PG) and thromboxane synthetases, were isolated from the bulb of Allium chinense G. DON, a Chinese medicinal drug. Stilbene derivatives structurally related to lunularic acid (3) were tested for inhibitory effect on prostaglandin synthetase. The compounds that inhibited PG biosynthesis also showed significant inhibitory effects on platelet aggregation induced by arachidonic acid and collagen.

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Four phenolic compounds were isolated from the stalks of Mucuna birdwoodiana TUTCHER, a Chinese medicinal drug used to treat so-called stagnant blood. Of the four compounds 2, 6-dimethoxyphenol and N- (trans-feruloyl) tyramine inhibited prostaglandin biosynthesis, and the former showed a potent inhibitory effect on in vitro platelet aggregation.

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6-Protoilluden-8α-ol (15) was formolyzed and then reduced with LiAlH₄ to give 7-protoilluden-6-ol (16) and its stereoisomer (17). 3-epi-6-Protoilluden-8a-ol (19) also gave the same products under the same conditions. These and other related reactions imply that the 7-protoilludene C-6 cation (10) is an important intermediate in the biosynthesis of illudane (11), marasmane (12) and illudalane (13) type sesquiterpenes.

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The reaction of 7- (methylsulfonyl) -1-phenyl-1H-1, 2, 3-triazolo [4, 5-d] pyridazine (1) with active methylene compounds or ketones (3a-g) in the presence of sodium hydride gave the corresponding 7-substituted 1-phenyl-1H-1, 2, 3-triazolo [4, 5-d] pyridazines (4a-g). A [4 + 2] cycloaddition occurred in the reaction with enamines or ynamines (9a-d) to give the corresponding arenotriazoles (10a-d). Similarly, the reaction of 7-chloro-1-phenyl-1H-1, 2, 3-triazolo [4, 5-d] pyridazine (2) with 3 and 9 resulted in the formation of 4 and arenotriazoles (12), respectively.

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1, 6-Dihydro-2-dimethylamino-4, 6, 6-trimethylpyrimidine reacted with acetylenic compounds containing electron-withdrawing groups to yield 2-dimethylaminopyridine derivatives. When monosubstituted acetylenes were used, 4-unsubstituted pyridines were selectively obtained. The results of MINDO/3 calculations are consistent with this regioselectivity.

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As a basic study on the efficient synthesis of chromogenic and fluorogenic peptidase substrates, we investigated possible general methods for the synthesis of α-amino acid and peptide amides of aromatic amines. Preparation of Boc-L-Leu-pNA (1) as a model compound was attempted by (1) the coupling of Boc-L-Leu-OH with p-nitroaniline, (2) the reaction of Boc-L-Leu OH with p-nitrophenyl isocyanate, and (3) the reaction of Boc-L-Leu-OH with the product formed from p-nitrobenzoic acid through the modified Curtius reaction with diphenyl phosphorazidate ((C₆H₅O) ₂P (O) N₃) in a one-pot process. The third method was found to be a general and efficient method for the preparation of α-amino acid amides of aromatic amines. Application of this method to the preparation of a peptidase substrate, Bz-L-Ile-L-Glu (OMe) -Gly-L-Arg-pNA (2), has also been successfully achieved.

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The acid-catalyzed rearrangement of triterpenoid monoenes belonging to the hopane and migrated hopane series with sulfuric acid and boron trifluoride etherate was investigated. By selecting the reaction conditions, a variety of the monoenes of these series, including three new compounds, 9βH-fern-7-ene (3c), 8βH-fern-9 (11) -ene (4b), and adian-5 (10) -ene (5b), were obtained. For comparison, oleanenes and migrated oleanenes were also subjected to the same reaction.

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The structure of oxyterihanine (2c), a new phenolic benzo [c] phenanthridone alkaloid which was isolated from Formosan Xanthoxylum nitidum (ROXB.) D. C. (Fagara nitida ROXB.), was established as 8-hydroxy-9-methoxy-5-methyl-2, 3-methylenedioxybenzo [c] phenanthridin-6 (5H) one by direct comparison with a synthetic specimen, which was derived from 2- (4-isopropoxy-3-methoxyphenyl) -6, 7-methylenedioxy-3, 4-dihydronaphthalen-1 (2H) -one (8a) through the synthetic sequence shown in Charts 3 and 4.
9-Hydroxy-8-methoxy-5-methyl-2, 3-methylenedioxybenzo [c] phenanthridin-6 (5H) -one [oxyisoterihanine (2d)] and two phenolic quaternary benzo [c] phenanthridine alkaloids, terihanine (1c) and isoterihanine (1d), were also synthesized.

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Highly lipophilic amines [trityloxyethylamine (TEAm) and N-trityloxyethylaniline (TEAn)] were introduced onto a 5'-phosphoryl group and the stability of the phosphoramidate linkage to acid was studied at the diester level. It was found that the phosphoramidate linkage using TEAn was cleaved by 80% aqueous acetic acid within 1 h at room temperature. However, it required 2 h to remove TEAm from the phosphate. By using the TEAn group, 5'-phosphorylated pentadecadeoxyribonucleotide pTCCAGGGTCTGGTAC was synthesized on a polystyrene support by the phosphotriester method. After partial deblocking, the pentadecamer with the TEAn group could be easily isolated on a reversed-phase column due to the high lipophilicity of the TEAn group.
The chemically synthesized 5 '-phosphorylated pentadecamer was successfully joined by using deoxyribonucleic acid ligase in the presence of a template.

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The alkylation of 2-arylcyclohexanones (12b and 6) with alkyl halides or acrylonitrile and 50% aq. sodium hydroxide in the presence of a phase-transfer catalyst (18-crown-6) was found to give readily 2-alkyl-2-arylcyclohexanones (14 and 16) in fair to good yields. Furthermore, 2-allyl-2-aryl-5, 5-ethylenedioxycyclohexanone (16a or 16b) was coverted into (±) -mesembrine (1), (±) -dihydromaritidine (4a), and (±) -epidihydromaritidine (5a) or (±) -elwesine (dihydrocrinine) (4b) and (±) - epielwesine (5b), respectively, via 5, 5-ethylenedioxy-2-formylmethyl-2- (3', 4'-dimethoxy- or 3', 4'- methylenedioxyphenyl) cyclohexyl acetate (20a or 20b).

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Six minor monosides (L-thevetosides of oleagenin and of 8β-hydroxy-17β-and 17α-digitoxigenin, L-acofriosides of 17β-and 17α-digitoxigenin and of tanghinigenin) were isolated from the airdried leaves of Cérbera odollam GAERTN. and C. manghas L., along with the major monosides, 17β-and 17α-neriifolin and 17β-and 17α-deacetyltanghinin.

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(±) -endo- (4) and (±) -exo-Brevicomin (5) were synthesized by employing the ene-type reaction of 4-chlorophenylthiomethyl trifluoroacetate (2) as the key step. The ene product 7 was converted, via two steps, into the ketosulfone 9, whose epoxidation followed by acid hydrolysis afforded the cyclic acetal as a mixture, 12a and 12b (89 : 11). Recrystallization of the mixture followed by desulfurization yielded (±) -endo-brevicomin (4). On the other hand, successive treatment of 9 with osmium tetroxide, hydrochloric acid, and Raney nickel afforded a mixture of (±) -exo- (5) and (±) -endo-brevicomin (4) (89 : 11).

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The synthesis of (±) -9-demethylprotoemetinol [(±) -3d] was accomplished by LiAlH₄ reduction of the tricyclic ester (±) -5 and subsequent debenzylation of the resulting tricyclic alcohol (±) 10. Acetylation of (±) -3d with acetic anhydride and pyridine gave the diacetate (±) -11. The same sequence of reactions starting with (-) -5 afforded (-) -9-demethylprotoernetinol [(-) -3d] and the diacetate (-) -11 through (-) -10. Parallel synthetic routes starting with the isomeric tricyclic esters (±) -9 and (-) -9 produced (±) -and (-) -10-demethylprotoemetinols [(±) -4d and (-) -4d] and the corresponding diacetates [(±) -13 and (-) -13] through (±) -12 and (-) -12, respectively. The correctness of the structure and absolute stereochemistry of an Alangium alkaloid inferred to be 10-demethylprotoemetinol was confirmed by a direct comparison of its diacetate with synthetic (-) -13.

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Three new phenolic compounds, 3'-Ο-methylsappanol, 3'-Ο-methylepisappanol and 3'-Ο-methylbrazilin, were isolated from Sappan Lignum, the dried heartwood of Caesalpinia sappan. The absolute configurations of sappanol, episappanol, 3'-deoxysappanol, 3'-Ο-methylsappanol, 3'-Ο-methylepisappanol, brazilin and 3'-Ο-methylbrazilin were determined by means of Horeau's partial resolution method and chemical correlations.
Sappanol, episappanol, 3'-deoxysappanol, 3'-Ο-methylsappanol and 3'-Ο-methylepisappanol form a novel class of homoisoflavonoids.

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A series of 1- (2, 3, 4-trimethoxybenzyl) piperazine (trimetazidine) derivatives were prepared and tested for cerebral vasodilating activity. Almost all the compounds possess stronger activity than trimetazidine and among them, the γ-amino tertiary alcohols 6e-j exhibit potent cerebral vasodilating activities which are superior to those of cinnarizine and papaverine. Moreover, these compounds show a selective vasodilating effect on vertebral arteries.

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Analogs of 1-[ (3-alkyl-3-hydroxy-3-phenyl) propyl]-4- (2, 3, 4-trimethoxybenzyl) piperazine (1) were prepared and tested for cerebral vasodilating activity. It was found that the potency depends positively on the number of methoxyl groups on the benzyl moiety, and the homopiperazine analogs seem to be equipotent to the corresponding piperazines.
From the standpoints of potency and ease of synthesis, 8k was selected for further study. Further analogs, which have various substituents in place of the benzyl moiety of 8k, were prepared and tested for cerebral vasodilating activity. These analogs were less potent than 8k. It was suggested that the benzyl moiety of 8k plays an important role in the high cerebral vasodilating activity.

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Quantitative structure-cerebral vasodilating activity relationships of 1-benzyl-4- (3-hydroxy-3-phenylpropyl) piperazines were examined. The analyses indicate that the potency depends on the number of methoxyl groups on the benzyl moiety, and the local lipophilicity around the asymmetric carbon atom is also of importance.
This work reveals that even initial screening data at a single dose can be analyzed quantitatively.

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The protected hexadecapeptide ester corresponding to positions 11 through 26 of human α₂-plasmin inhibitor fragment T-11, which consists of 26 amino acids and binds to the plasmin (ogen) lysine-binding site (s), was synthesized by assembling five peptide fragments by the azide method or the dicyclohexylcarbodiimide-N-hydroxybenzotriazole method.

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The hexacosapeptide corresponding to the entire amino acid sequence of human α₂-plasmin inhibitor fragment T-11 was synthesized by a conventional solution method. Three newly synthesized fragments were combined successively with the protected C-terminal hexadecapeptide ester previously obtained by using the dicyclohexylcarbodiimide-N-hydroxybenzotriazole and azide procedures to afford the protected hexacosapeptide ester. The trifluoromethanesulfonic acid-thioanisole-trifluoroacetic acid procedure was employed to remove all protecting groups of the protected peptide ester at the final stage. The dissociation constant for the interaction between the synthetic α₂-plasmin inhibitor fragment T-11 and plasmin was equal to that of the native T-11 from human α₂-plasmin inhibitor.

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Twelve shortened fragments of peptide T-11, which is a part of human α₂-plasmin inhibitor and contains its plasmin (ogen) -binding site (s) were synthesized by a conventional solution method. The dissociation constants for the interaction between these synthetic fragments and plasmin were determined. Among these fragments, the octadecapeptide containing C-terminal lysine of T-11, which consists of 26 amino acids, was found to be the smallest active fragment of T-11. The N-terminal and the central portion fragments of T-11 possessed no binding activity. The heptadecapeptide which has the same sequence as the octadecapeptide but lacks the C-terminal lysine showed no binding activity. The hexadecapeptide containing the C-terminal lysine but lacking the 10th lysine in T-11 scarcely exhibited the activity. Thus, the lysine residues at positions 10 and 26 in T-11 must be important for the activity.

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Various 3-phenyl-2-piperazinylquinolines and their 3-methyl analogs were synthesized and the effects of these compounds on the central nervous system were evaluated pharmacologically in mice. Some compounds having a 3-phenyl group showed potent antagonism of maximal electroshock seizures, but the 3-methyl analogs had no significant activity in any of the tests.

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Examination of the structure-activity relationships of 2- (phenylpiperazinoalkoxyphenyl) -thiazolidine-3-carbothioamides and the corresponding carboxamides (1) as new cardiotonic agents was extended by the chemical modification of the phenylpiperazino moiety. The 4-phenylpiperidine (13), 4-phenyltetrahydropyridines (17), and related derivatives were prepared from the chlorides (10) through several intermediates (12, 14, and 16) and tested for cardiotonic activity. Generally, both the 4-phenylpiperidine (13) and 4-phenyltetrahydropyridine (17) derivatives exhibited potent positive inotropic activity comparable to that of 1. The N-phenylpiperidines (9) and amide derivatives (22, 25, and 28) exhibited no significant positive inotropy. This is also the case for the phenylpropylamines (29) and the ethylenediamines (30), which are pseudo-ring analogues of 1 with respect to the piperazine moiety. The activity of the homopiperazine derivative (23) was approximately one-thirtieth of that of the corresponding piperazine derivative (1). Thus, the presence of the six-membered, basic azacycloalkane ring (piperidine or piperazine) with a 4-phenyl group at the end of the alkoxy side chain appears to be essential for the appearance of potent positive inotropic activity in this series of compounds.

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A series of dithiocarbamates of α-amino acids was synthesized and tested for hepatoprotective activity against CCl₄-induced liver damage in mice. Reaction of the amino acids (2, 4, 6 and 8) with carbon disulfide followed by methylation gave the corresponding dithiocarbamates. Among the compounds synthesized, the β-carboline derivative (9a) exhibited remarkable hepatoprotective activity. The oxa analogues (9b-d) with respect to the dithiocarbamate group of 9a were also prepared. The activity of 9a-d decreased in the following order : dithiocarbamate (9a) > S-methyl thiocarbamate (9b) > O-methyl thiocarbamate (9c) > carbamate (9d). The structure-activity relationships are discussed.

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A mutagenic principle in the neutral fraction of the methanol extract from Sinomeni Caulis et Rhizoma (Menispermaceae) was isolated by conventional techniques, and identified as a new dehydroaporphine alkaloid, N-demethyl-N-formyldehydronuciferine, on the basis of mass, ultraviolet, proton and carbon-13 nuclear magnetic resonance spectra, and X-ray analysis. N- Demethyl-N-formyldehydronuciferine was mutagenic to Salmonella typhimurium TA98 and TA100.

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Three novel guaiane-type sesquiterpenes, hanalpinone (I), isohanalpinone (II), and alpinenone (III), and two novel secoguaiane-type sesquiterpenes, alpinolide peroxide (IV) and 6-hydroxyalpinolide (V) have been isolated from the rhizomes of Alpinia japonica. Their structures were determined by spectroscopic methods, chemical conversions, and X-ray analysis. Their biosynthetic relationships with previously identified sesquiterpenes from Alpinia japonica are discussed.

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Three novel sesquiterpene peroxides, hanalpinol peroxide (I), isohanalpinol (II), and aokumanol (III), a new secoguaiane-type sesquiterpene, epialpinolide (IV), and a new elemophilane-type sesquiterpene, Δ^{11 (12)} -eremophilen-10β-ol (V), have been isolated from the rhizomes of Alpinia intermedia together with eight known sesquiterpenes, hanalpinol (VI), hanalpinone (VII), isohanalpinone (VIII), alpinenone (IX), furopelargone B (X), furopelargone A (XI), intermedeol (XII) and β-selinene (XIII). The structures of I-V were determined by spectroscopic methods, chemical conversion, and X-ray analysis. Their biosynthetic relationships are discussed.
From the point of view of chemotaxonomy, it is suggested that Alpinia intermedia and Alpinia japonica are closely related plants.

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Four new sesquiterpene glycosides, sonchusides A (6), B (7), C (8) and D (9), have been isolated from Sonchus oleraceus L., together with five known glycosides, glucozaluzanin C (1), macrocliniside A (2), crepidiaside A (3) and picrisides B (4) and C (5). The structures of the new compounds were established on the basis of chemical and spectral data.

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The interaction of homopolynucleotides complexes and ellagitannins was studied by circular dichroism (CD) spectroscopy. The interaction difference CD spectra of mixtures of (rC)_n (dG)_n and dimeric ellagitannins showed extremely large positive peaks especially around 250 nm, suggesting a strong interaction. The mixtures with (rA)_n (dT)_n also had large difference CD spectra, although the interaction showed no apparent contribution to the stabilities of the nucleotides complexes.

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Larvicidal principles obtained from the 50% aqueous acetone extract of betel nuts (Areca catechu) were revealed to be a mixture of fatty acids. They were identified by GC-MS analysis as lauric, myristic, palmitic, and oleic acids. Determination of the larvicidal activities of fatty acids and aliphatic alcohols with various alkyl chain lengths, and of analogous compounds with various functional groups, suggested that the balance between hydrophilicity and hydrophobicity is important for the larvicidal activity.

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Postheparin plasma lipolytic activity consists of hepatic triglyceride lipase (H-TGL) and lipoprotein lipase (LPL) activities. The effect of chlorinated pesticides, pentachlorophenol (PCP) and 1, 1, 1-trichloro-2, 2-bis- (4-chlorophenyl) ethane (DDT), on these lipase activities in rat postheparin plasma was examined. PCP completely inactivated H-TGL but did not change LPL activity. On the other hand, DDT completely inactivated LPL but did not change H-TGL activity. By utilizing these specific inhibitions, a procedure for selective measurement of H-TGL and LPL in postheparin plasma of young and old rats, with and without diabetes, was developed. The values of H-TGL and LPL activity obtained by this method were in good agreement with those obtained by immunochemical methods.

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Twenty two 3-Ο-alkyl derivatives of D-glucose and D-allose, four 3-Ο-alkenyl derivatives of D-glucose having an end methylene group, and four 3-Ο-ω-hydroxyalkyl- or -methoxyalkyl derivatives of D-glucose were synthesized. Their cytotoxicity in vitro against the cultured leukemia L-5178Y cell line, antimicrobial activity and plant growth-inhibitory effect were determined.

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Basal and maximum corticosterone secretions of the whole pituitary-adrenal cortex system or the adrenal cortex were determined in rats treated with saikosaponin d (saiko-d) from Bupleurum falcatum L. alone or with dexamethasone for 5 or 9 d. In rats treated with 0.5, 1.0 or 2.5 mg/kg/d of saiko-d, or saiko-d and 0.025 mg/kg/d of dexamethasone for 5 d, both basal and acutely stimulated evening levels of plasma corticosterone on day 5 were very slightly below normal; the stimulated level due to saiko-d was significantly higher than the basal level, but was not significantly lower than the normal and adrenocorticotropin (ACTH) -stimulated maximum level. In rats chronically treated with saiko-d (2.5 mg/kg/d) alone, or with saiko-d and a high dose of dexamethasone (0.05 mg/kg/d) for 9 d, the stimulated level of corticosterone was nearly equal to the basal level, and saiko-d administered with dexamethasone reduced the adrenal weight on day 9. These chronic effects of saiko-d on the adrenal activity and weight were fully effective in the early phase, but were less effective and then suppressive in the late phase, especially at a high dose of saiko-d or on coadministration of saiko-d and dexamethasone.

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In vitro release characteristics of prednisolone (PD) and its β- and γ-cyclodextrin (β- and γ-CyD) complexes were investigated by using an ointment release simulator with artificial doublelayer membranes. The release of PD from hydrophilic ointment was significantly improved by β-and γ-CyD complexations. Permeation and uptake studies indicated that the enhanced release of PD from the ointment may be mainly due to the faster dissolution of PD in the base and the lower binding affinity of PD to the ointment base as a result of the CyD complexations. The percutaneous absorption of PD from hydrophilic ointment after application to the rabbit skin was also increased by CyD complexations. The in vitro and in vivo data suggest that CyDs can improve the topical bioavailability of PD.

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Uptake of cefmetazole into isolated rat intestinal epithelial cells increased with increasing nonprotein thiol loss induced by diethyl maleate (DEM) at concentrations up to 1 mM. However, 5 mM DEM decreased cefmetazole uptake, accompanied with a loss of protein thiol, despite the loss of nonprotein thiol. The coaddition of calmodulin inhibitors such as trifluoperazine (TFPZ) and chlorpromazine (CPZ) with 5 mM DEM restored cefmetazole uptake and inhibited protein thiol loss. The administration of DEM at 0.75 mM into the lumen of a rat ileal loop increased cefmetazole absorption along with loss of nonprotein thiol in the tissue. However, significant protein thiol loss occurred on administration of 7.5 mM DEM, and cefmetazole absorption was decreased. The appearance of cefmetazole in plasma after an injection of cefmetazole into connective tissue of the ileal loop was also inhibited by preadministration of 7.5 mM DEM into the loop. Coadministration of calmodulin inhibitors at a concentration of less than 100 μM with 7.5 mM DEM inhibited protein thiol loss Kut not nonprotein thiol loss. Coadministration of calmodulin inhibitors with 7.5 mM DEM increased cefmetazole absorption from the ileal lumen, and restored cefmetazole appearance in the plasma after injection into connective tissue. Thus, nonprotein thiol loss in cells and tissue of the intestine increased cefmetazole absorption from the mucosal lumen into the blood circulation, but protein thiol loss inhibited it.

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The effect of the infusion rate on the relationship between plasma concentration (Cp) and positive inotropic action (PIA) of ouabain was studied in rabbits. The maximum of the first derivative of the left ventricular pressure (dP/dt_max) was used as an index of PIA. The Cp of ouabain was measured by counting the radioactivity of ³H-ouabain, a nonmetabolizable cardiac glycoside. ³H-Ouabain was infused via the femoral vein at 2.7, 13 and 38 nmol/min/kg, and the time courses of Cp and dP/dt_max were measured simultaneously. Non-linear initial volume of distribution was suggested from the different slopes of the Cp curves normalized by infusion rate during the initial 5 min. The relationship between Cp and PIA depended remarkably on the infusion rate. The values of Cp which produced the maximum PIA at the low, medium and high infusion rates were 136± 18, 700 ± 210 and 2300 ± 545 nM (mean ± S.E.M.), respectively. The total amounts of infused ouabain until the maximum PIA at the low, medium and high infusion rates were 81 ± 6.8, 130± 6.5 and 152 ± 7.2 nmol/kg (mean ± S.E.M.), respectively. It was clear that ouabain does not exhibit its action in the central compartment, although it is considered to be a fast-acting cardiac glycoside. It is suggested that a slow step exists in the appearance of PIA of ouabain in rabbits.

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The effects of two kinds of fatty acids (stearic acid and palmitic acid) added to mixture of fatty alcohol and propylene glycol (FAPG base) on the percutaneous absorption of indomethacin (ID) were investigated by using the normal abdominal skin of rats in vivo. The percutaneous absorption of propylene glycol (PG) from FAPG base was simultaneously examined.
The percutaneous absorption profiles of ID from No. 1 (consisting of stearyl alcohol and 75% PG) and from No. 2 (consisting of stearyl alcohol, stearic acid and 75% PG) bases were almost the same. On the other hand, the absorption of ID from No. 3 base (consisting of stearyl alcohol, palmitic acid and 75% PG) was significantly higher than those from Nos. 1 and 2 bases. Furthermore, PG was readily absorbed through the rat skin from Nos. 1, 2 and 3 FAPG bases and its percutaneous absorption profiles were similar to those of ID.
In order to establish the reason for the differences in percutaneous absorption of ID from the three bases, the apparent partition ratio of ID between water and vehicle was determined as a parameter of the affinity of ID for the vehicle. There was no difference in apparent partition ratio between Nos. 1 and 2 bases, while that of No. 3 base was the highest among the vehicles tested. The release of ID from Nos. 1, 2 and 3 bases in vitro was also studied by using a silicone rubber membrane. The results of the in vivo test were broadly consistent with those of the in vitro tests.

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Palmitoyl amino acids and palmitoyl glutathione were synthesized. Liposome-like vesicles based on these compounds were prepared and their barrier functions were examined. These vesicles showed encapsulation efficiencies for aqueous solute comparable to that of conventional phosphatidylcholine liposomes (PC-liposomes). They were also stable in fresh rat plasma at 37°C.
The biological behavior (blood clearance, urinary excretion and tissue distribution) of the vesicles based on palmitoyl serine (PSer-liposomes) or palmitoyl glutathione (PGSH-liposomes) was examined after intravenous injection in rats. The synthetic liposomes were cleared very rapidly from the blood compared with PC-liposomes. PSer-Liposomes showed a large amount of urinary excretion of aqueous marker ([³H] inulin), suggesting that the mechanisms of vesicle degradation in vivo and in vitro are different. These synthetic liposomes showed low affinity to the spleen and high affinity to the liver in the tissue distribution study, and thus they may be expected to be a useful drug carrier which is targetable to the liver.
A suppressing effect of PGSH-liposomes on the increase of plasma glutamate oxaloacetate transaminase (GOT) induced by a high dose of acetaminophen in mice was observed, and transport of glutathione into the liver cells apparently occurred. The suppressing effect was greater than that of free glutathione or PC-liposomes containing free glutathione. However, the effect was not observed in the case of PGSH-liposomes without phosphatidylcholine, which appears to have an important role in the liposome-cell interaction.

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Bioinequivalence of glassy and crystalline indomethacin was investigated in rabbits. In vivo absorption studies were carried out by determining the plasma levels of indomethacin following oral and rectal administrations in rabbits. The AUC (area under the concentration-time curve) and the maximum plasma level following the administration of the glassy preparation were larger than those in the case of the crystalline preparation. The amounts of indomethacin absorbed were calculated by the deconvolution method. It was shown that the amounts absorbed following oral and rectal administrations of the glassy preparation were larger than those in the case of the crystalline preparation. These results indicated that the bioavailability of the glassy indomethacin was better than that of the crystalline indomethacin.

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Phenacetin and lactose powders, as models of slightly and highly water-soluble drugs, respectively, were coated by means of the Wurster process.
Phenacetin (80-250 mesh) was a fragile crystalline material and hence fluidization had to be moderate. As a result, the agglomeration of some particles or the adhesion of small particles to large particles could not be avoided. However, the particles coated with triacetin (plasticizer) -containing lacquer (60% as dry lacquer relative to the core material) released only 6.0% of phenacetin in JP XI disintegration medium No. 1. This result suggested that slight agglomeration did not prevent the encapsulation. When a polyethyleneglycol 6000 and polysorbate 80 mixture was used as a plasticizer in the coating of phenacetin, the membrane became more permeable than when triacetin was used.
With lactose (100 mesh), which is a comparatively hard crystalline material, discretely encapsulated particles could easily be produced. The lactose particles coated with triacetin-and with polyethyleneglycol 6000-polysorbate 80-containing lacquer exhibited identical dissolution properties. Their dissolution profiles were characterized by a lag time, which increased with the amount of coating applied, followed by a rapid release. This lag time was the period needed for lactose crystals to be dissolved in rapidly taken up water. The inward flow of water should prevent lactose from diffusing out during the lag time. The high solubility and high permeation rate of lactose and the large specific surface area of particles produced by the Wurster process presumably account for the rapid release after the lag time. These dissolution profiles of coated lactose particles suggested that they should be useful as a model to study oral drug delivery systems with various lag times of dissolution.

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An alternative nonanimal test to the Draize test to evaluate the eye irritancy of surfactants has been newly developed. The physicochemical lysis of liposomal membranes by various surfactants, such as sodium dodecyl sulfate (SDS), dodecyldimethylbenzylammonium chloride (BTC), tetradecyldimethylbenzylammonium chloride (Sanisol M-100), benzyldimethy1-2- (2-p-1, 1, 3, 3-tetramethylbutylphenoxy) ethoxyethylammonium chloride (Hyamine 1622), dodecanoyldiethanolamide (LDE), and polyoxyethylene (n=21) -sorbitan monostearate (Tween 80), was correlated with the results of the Draize test with the same surfactants. Egg phosphatidylcholine small unilamellar vesicles (SUVs) coated with O-palmitoylamylopectinsulfonic acid were employed as a model of the human corneal epithelium. The lysis of liposomes with the surfactants was monitored quantitatively by following the release of carboxyfluorescein (CF) from the interior water phase of the liposomes suspended in an aqueous medium containing almost the same salt composition as that in the human tear film. The order of efficiencies of these surfactants in perturbing the liposomal membrane was Sanisol M-100 > Hyamine 1622 >BTC> (Tween 80>) LDE>SDS. With the exception of Tween 80, whose critical micelle concentration (cmc) is relatively low (9.6 × 10^-6M) compared with those of the other surfactants (approximately 5-7× 10^-4M), a reliable correlation was found between the results of animal and nonanimal tests.

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When saturation binding studies of β-adrenoceptors in rat brain with ¹²⁵I-iodocyanopindolol (¹²⁵I-ICYP) were carried out by means of radioligand binding assay, the Scatchard plots showed a biphasic character. The addition of guanosine triphosphate (GTP, 3× 10^-4 M) had no effect on the biphasic character. The inhibition constants of various ligands for the high-and low-affinity sites of ¹²⁵I-ICYP binding were determined from the biphasic Scatchard plots. Competition by the agonists at the high-affinity sites was in the order of l-isoproterenol> l-epinephrine > l-norepinephrine, whereas at the low-affinity sites, the order was l-isoproterenol > l-epinephrine = l-norepinephrine. The specificities of the agonists for the high-and low-affinity sites were high = low (l-isoproterenol), high >low (l-epinephrine), or high < low (l-norepinephrine). These results suggest that two distinct types of β-adrenoceptor sites can be differentiated in rat cerebral cortical membranes.

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N- (3-Piperidinopropyl) -4-methyl-6-trifluoromethyl furo [3, 2-b] indole-2-carboxamide (FI-302) is a new non-steroidal anti-inflammatory compound. The analgesic effect of FI-302 and its effect on the central nervous system (CNS) were compared with those of aspirin, chlorpromazine and chlordiazepoxide in mice subjected to various experimental conditions. FI-302 showed an analgesic effect with all the methods used, but aspirin, chlorpromazine and chlordiazepoxide showed analgesic effects only with the acetic acid-induced writhing method. Moreover, FI-302 inhibited spontaneous motor activity and fighting behavior induced by isolation and foot-shock, but had no effect on the hexobarbital-induced sleeping time. Aspirin had no effect on the CNS, but chlorpromazine and chlordiazepoxide showed inhibitory effects with all the methods used. Fighting behavior is related to emotional response, and pain is associated with emotional responses such as distress and anxiety. Thus, it is suggested that FI-302 is a new analgesic compound which has an inhibitory effect on the emotional response in the CNS.

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The binding affinities of racemic derivatives of propranolol to β-adrenoceptors were examined by means of radioligand binding assay to determine whether racemic propranolol shows biphasic binding to β-adrenoceptors in a displacement experiment. Rat brain was used and the β-adrenoceptor binding assay was carried out with ³H-dihydroalprenolol as the radioligand. A higher affinity of l-propranolol than of d-propranolol was observed and d-and l-propranolol each gave a uniphasic curve. However, dl-propranolol showed a biphasic curve. Furthermore, a mixture of d-and l-propranolol also showed a biphasic curve. These results imply that β-adrenoceptors of rat brain may bind the d-and l-isomers at distinct sites.

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In connection with the teratogenic activity of thiabendazole (TBZ), the metabolic fate of ¹⁴C-TBZ in pregnant mice was studied by administration of the drug in olive oil and gum arabic as vehicles. Absorption of TBZ in the olive oil group occurred more rapidly than in the gum arabic group, and the maximum blood level in the former group was 7-fold higher than that in the latter group. 5-Hydroxylated TBZ (5-HY TBZ), its glucuronide and its sulfate were identified as urinary and fecal metabolites. A very small quantity of N-methyl TBZ was also identified for the first time in the urine and feces. The percentages of TBZ, 5-HY TBZ, and the glucuronide and sulfate of 5-HY TBZ in the urine were 12-15, 22-24, 28-29 and 30-31%, respectively. About 97% of the dose was excreted into the urine (60-62%) and the feces (34-37%) within 7 d in each group. In a limb bud cell culture system for the assay of teratogenic potential, the concentrations of TBZ, 5-HY TBZ and N-methyl TBZ necessary to reduce the amounts of cartilage proteoglycan by 50% were estimated to be about 0.09, 0.09 and 0.24 mM, respectively. However, the concentrations of 5-HY TBZ glucuronide and sulfate were over 2 mM. Consequently, teratogenesis caused by TBZ appeared to be induced by the high levels of direct-acting teratogens such as TBZ and 5-HY TBZ when olive oil was used as a vehicle.

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