A novel agglomerated crystallization technique, termed spherical crystallization technique, which can transform fine crystals precipitated into spherical agglomerates in one step during the crystallization process, has been developed by using new agglomeration phenomena of particles in liquid system. In this technique, a binary or a ternary mixture of partially miscible solvents was used as a crystallization solvent. It was found that by choosing the proper proportion of the mixture, a small amount of immiscible liquid was liberated from the system, which could preferentially wet the crystals, forming spherical agglomerates. By using this technique, needle like crystals of salicylic acid were agglomerated into spheres being directly compressible into tablet. Spherically agglomerated crystals of aminophylline were prepared directly by reacting theophylline with ethylenediamine in an alcohol-organic solvent-water mixture. The spherically agglomerated crystals of new complex of indomethacin and epirizole with increased solubilities were prepared. Controlled release microspheres of ibuprofen with acrylic polymer were prepared to improve bioavailability.
Galactosaminoglycan (CO-N), prepared from the culture filtrate of Cordyceps ophioglossoides, aggregated the sera from cancer patients, but not those from healthy donors. The results of sodium dodecyl sulfate polyacrylamide gel electrophoresis, polyacrylamide gel isoelectric focusing, and single radial immunodiffusion revealed that the aggregate mainly consisted of haptoglobin, albumin, α1-acid glycoprotein, α1-antitrypsin, hemopexin, and CO-N itself. The pre-addition of h-CO-N (Mr ca. 10000, polygalactosamine obtained by partial acid hydrolysis of CO-N) resulted in inhibition of the aggregation by CO-N. Desialylation of the serum by neuraminidase treatment also resulted in inhibition of the aggregation. Further h-CO-N, N-acetylated CO-N, chitosan, or diethylaminoethyl-dextran instead of CO-N was added to the serum, the aggregation was not observed. When α1-acid glycoprotein was added to the serum from healthy donor, the aggregation by CO-N was observed, while haptoglobin or α1-antitrypsin did not cause aggregation. These results suggested that the binding between galactosaminyl residues of CO-N and sialic acids at non-reducing ends of sugar chains of serum glycoproteins might be required as the essential step to the aggregation by CO-N.
The stability and degradation of oral cephalosporin, pivaloyloxymethyl (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylate (T-2588) and its parent compound, (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylic acid (T-2525) were studied. The aqueous solutions of T-2588 and T-2525 were kept at 35°C, and their degradation patterns were investigated by use of high performance liquid chromatography. T-2588 was stable in the range of pH 2.0-5.5, and unstable at above pH 5.5, while T-2525 was stable in the range of pH 4.0-6.0, and slightly unstable beyond this range. It was confirmed that pivaloyloxymethyl (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamidol-3-[(5-methyl-2H-tetrazol-4-yl) methyl]-2-cephem-4-carboxylate (T-2588A), 2-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-245-(5-methyl-2H-tetrazol-2-yl) methyl-4-pivaloyloxymethoxycarbonyl-2, 3-dihydro-H6-1, 3-thiazin-2-yl] acetic acid (T-2588C), (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-2-cephem-4-carboxylic acid (T-2525A), (Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-N-formylmethylacetamide (T-2588G) and T-2525 were produced in alkaline and acidic solution of T-2588, and that T-2525A, T-2588G and (6R, 7S)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylic acid (T-2525H) were produced in alkaline solution of T-2525, and T-2588G was produced in acidic solution of T-2525.
The metabolism of pivaloyloxymethyl (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylate (T-2588), a new oral esterified cephalosporin as a prodrug of (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylic acid (T-2525), was studied. Metabolites in the urine and feces of mouse, rat, rabbit and dog, which were orally given T-2588, were detected by high performance liquid chromatography. In the urine, T-2525 was excreted as a main metabolite, while (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-2-cephem-4-carboxylic acid (T-2525A) was excreted slightly. The in vitro and in vitrostudy of T-2588 showed that T-2588 and pivaloyloxymethyl (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetrazol-2-yl) methyl]-2-cephem-4-carboxylate (T-2588A), a degraded product in gastrointestinal content, were absorbed from upper gastrointestinal tract, and hydrolyzed to T-2525 and T-2525A by esterase, respectively, and excreted in the urine after systemic circulation. Unabsorbed T-2588 and T-2588A were also hydrolyzed to T-2525 and T-2525A by esterase in gastrointestinal tract. These products were partly excreted in the feces, while most of these products were degraded by β-lactamase produced by intestinal flora.
The metabolism of pivaloyloxymethyl (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-methy1-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylate (T-2588), a new oral esterified cephalosporin of T-2525 as a prodrug, was studied with 14C-T-2588. 14C-Activity was recovered mostly in the feces, a little in the urine and slightly in the bile, when (aminothiazole-2-14C)-T-2588 was orally given to rats and mice. 14C-T-2588 was rearranged to 14C-T-2588A by gastrointestinal content. 14C-T-2588 and 14C-T-2588A were absorbed at the upper intestine, and hydrolyzed to 14C-T-2525 and 14C-T-2525A, respectively, by esterase in the intestinal mucosa. 14C-T-2525 and 14C-T-2525A were circulated in whole body and excreted into the urin. On the other hand, unabsorbed 14C-T-2588 and 14C-T-2588A were hydrolyzed by esterase in the intestinal tract to 14C-T-2525 and 14C-T-2525A, respectively, which were excreted partly in the fbces and metabolized mostly by β-lactamase produced from intestinal flora to unidentified metabelites. One of unidentified metabolites was assumed to be (Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-N-formylmethylacetamide (T-2588G). 5-Methyl-1H-tetrazole (T-2588F) and pivalic acid were produced together with liberation of T-2588G, and absorbed at the intestine. Unchanged T-2588F and conjugated pivalic acid were excreted into the urine. 14C-Activity was almost recovered in respiratory air, when (pivaloyhxymethyl-14C)-T-2588 was orally given to rats and mice. It is assumed that HCHO, produced from 14CT-2588 by esterase, was metabolized to CO2.
Polyvinyl alcohol (PVA) aqueous solutions with high water content were repeatedly frozen and defrosted to obtain PVA hydrogels with high elasticity. Tack and viscoelasticities such as storage modulus and loss tangent of the PVA hydrogels were determined as a function of molecular weight, saponification value of PVA, number of cycles of freezing-defrosting procedure or temperature of defrosting, in order to obtain an information on utilities of the materials as prepared poultices and transdermal therapeutic system. Correlation matrix method of multiregression analysis was applied to our data on tack and viscoelasticities of gels, and it was found that there was a significant correlation between tack and storage modulus as well as loss tangent of the materials. Tack, which is one of the most essential properties of pressure sensitive adhesives as prepared poultices and drug delivery system, can easily be predicted, if we measure viscoelasticities of the materials.
The aim of this study was to evaluate the effect of 50% methanolic extract of “Bai-Zhu” originating from Atractylodes ovata (AO) on the levels of 11-OHCS and that of gastrin in the plasma, gastric mucosal blood flow in rats with water-immersion stress and on the development of acute gastric mucosal lesions after a short period of waterimmersion restraint stress. In rats administered AO orally, neither effects on the levels of 11-OHCS and gastrin in the plasma nor a change in gastric mucosal blood flow were observed, while in rats with water-immersion stress, AO prevented an increase in levels of 11-OHCS and gastrin, a decrease in gastric mucosal blood flow and the development of gastric mucosal lesions. These findings indicate that AO exhibited the anti-ulcerogenic activity against stressulcer in preventing abnormal change in plasma levels of steroidal hormones and in remeding insufficient state of circulatory system caused by stress.
Barbituric acid (BA), allobarbital (AlloB) and seven kinds of allyl substituted barbituric acid were prepared and their pharmacological activity (hypnotic and anticonvulsant activities) was evaluated in mice. The interactions of BA and these allyl substituted barbituric acids with several barbiturates were also studied. Among them, N, 5, 5-triallyl-BA (6) exhibited some hypnotic and anticonvulsant activities, but the other compounds did not show any activity. BA (160mg/kg, i. p.) was found to possess a prolonging effect on pentobarbital (PB)-induced sleep. N-Allyl-BA (1), 5-Allyl-BA (2), N, N', 5-triallyl-BA (5), 6and N, N', 5, 5-tetraallyl-BA (7)(60 or 160mg/kg, i. p.) also prolonged PB-induced sleeping time. Compound 6 was most potent on interaction with all barbiturates used, except for barbital (B). Compound 7 prolonged AlloB-, PB- and amobarbital (AB)-induced sleeping time, but not the other barbiturates-induced sleeping time. The prolonging effects of BA, 6 and 7 on PB-induced sleep were dose-dependent. Compounds 3-5 exhibited a prolonging effect on thiopental (TP)-induced sleep. Although compound 3 prolonged phenobarbital (PheB)-induced sleeping time, the compound and 4 did not show any prolonging effect on PB-induced sleep. These results indicate that the position and number of allyl group substituted play an important role in their depressant activity, and that BA itself possesses some depressant activities.
The mode of uptake of mitomycin C (MMC) was examined by use of rat ascites hepatoma AH130 cells. The uptake of MMC into AH130 cells increased in proportion to the cell number and the extracellular concentration of MMC. The uptake was nonsaturable and temperature-dependent but not inhibited by metabolic inhibitors such as ouabain, 2, 4-dinitrophenol, sodium azide or iodoacetic acid. MMC was rapidly metabolized in the cells and its metabolites accumulated with the time of incubation. Intact MMC in the cells was only a little. The uptake of MMC was, however, not affected by the metabolites accmulated in the cells. Amphotericin B potentiated the uptake and cytotoxicity of MMC. On the other hand, dibucaine diminished not only the uptake but also the cytotoxicity of MMC. These results suggest that MMC is taken up into rat ascites hepatoma AH130 cells in an energy-independent manner but the uptake is non-saturable because MMC is rapidly metabolized in the cells.
From the n-BuOH soluble fraction of aqueous extract of leaves of Desmodium styracifolium MERR (Leguminosae), three di-C-glycosylflavonoids, vicenin-1, vicenin-3 and schaftoside, which were ordinarily discovered in this genus, were isolated.