The polymeric forms of silicic acid in various silicate antacids were studied by the trimethylsilyation and silicomolybdate methods. Composition and distribution were markedly influenced by the kind of silicates. The low molecular weight silicic acids determined by the silicomolybdate method were estimated to include silicic acid molecules such as H4SiO4, H6Si2O7, H8Si3O10, H3Si4O12, and some linear polymer, and the forms of colloidal silicic acids were estimated to have H2n+4Si2nO5n+2. The trimethylsilylation method is excellent for the silicate structure analysis. It is possible to learn of a measure of the gastrointestinal absorption of silicic acid by the silicomolybdate method.
In order to examine biological activities, synthesis of 6-amino-2 (1H)-pyridones and their cyclization were carried out. The reaction of 4-cyano-3-butenoic acid esters (IIIa, b) with ammonia, methylamine, hydroxylamine, and hydrazine gave 6-amino-2 (1H)-pyridones (IVa, b) and the derivatives of IV having substituents such as methyl group (IVc), hydroxyl group (VII), or amino group (X) respectively, at 1-position. Condensation of these 1, 6-disubstituted 2 (1H)-pyridones with 1, 3-dicabonyl compounds or carboxylic acids resulted in the formation of 1, 8-naphthyridinone (VI), oxadiazolo [2, 3-a] pyridones (IX), or triazolo [2, 3-a] pyridones (XI).
Relationship between activities of oxidases and oxygen consumption in Lactobacillus acidophilus was examined. NADH oxidase activity (about 600 nmol/min/mg protein) was found in the extract of the cells grown in a medium containing glucose. This enzyme was cytochrome-independent and mainly found in the supernatant fluid obtained from homogenized cells by centrifugation at 105000×g. Its optimum pH was at 5.9 and its Km value for NADH was 2.04×10-5M. Both enzyme activity and oxygen consumption increased to the maximum at late logarithmic phase and rapidly decreased at the stationary phase. Oxygen consumption of the cells grown in a medium containing polyols was 2-4 times higher than that of the cells grown in a medium containing hexoses, and NADH oxidase activity of the former was also 2-4 times higher than that of the latter. Variation in the activity of NADH oxidase was roughly proportional to that of oxygen consumption. Oxygen consumption of the cells in the presence of pyruvate or lactate was also observed to be KCN-insensitive. Under these conditions, effect of carbon source used in the culture medium on oxygen consumption of the cells was similar to that in the presence of glucose. These results suggest that NADH oxidase is related to the oxygen consumption of L. acidophilus.
Glucocorticoids, e.g., dexamethasone (DM), fluocinolone acetonide (FA), triamcinolone acetonide (TA), cortisone (CS), and corticosterone (CST), were determined by gas chromatography including trimethylsilylation. In method A, a solution of 5-50 μg of each glucocorticoid and 5 μg of cholesterol as an internal standard dissolved in 0.2 ml of N, O-bis (trimethylsilyl) acetamide (BSA) or N, O-bis (trimethylsilyl) trifluoroacetamide (BSTFA) containing 5 mg of sodium acetate was heated at 60-80°for 2-3 hr. Two μl of the solution was analyzed by gas chromatography. In method B, 20 μl of the solution obtained in method A was transferred to a sample tube, evaporated under a stream of nitrogen, and the residue dissolved in 40 μl of carbon tetrachloride, 2 μl of which was analyzed by gas chromatography. FA was determined by method A, and DM, TA, CST, and CS by method B. Method B was applied to commercial DM tablets, and the results were compared with those obtained by UV and BT methods. The values by method B were lower than those by UV method, and were almost the same as those by BT method. The trimethylsilyl derivative of DM was proved to be a tetratrimethylsilyl compound by gas chromatography-mass spectroscopy.
Reaction of commercial quinoline derivatives (1a-r), dissolved in chloroform and added with ethanol and sodium hydroxide solution, in the presence of triethylbenzylammonium hydroxide, at room temperature resulted in the formation of 1, 1-dichloro-2-ethoxy-3-formyl-1a, 2, 3, 7b-tetrahydro-1H-cyclopropa [c] quinoline derivatives (2a-h) in one step, in a good yield. The use of methanol in place of ethanol gave 1, 1-dichloro-3-formyl-2-methoxy-1a, 2, 3-7b-tetrahydro-1H-cyclopropa [c] quinoline (9a). Examination of the effect of substituents in 1a to 1r on the formation of cyclopropa [c] quinoline derivatives by this reaction showed that the reaction with dichlorocarbene did not proceed as expected when there was an electron-attracting group like NO2 in the benzene ring of 1a to 1r, while the compounds like 2a to 2h were formed when there was an electron-donating group like CH3 and CH3O was present. Application of methylmagnesium iodide to 2a in ether produced 1, 1-dichloro-2-methyl-1a, 2, 3, 7b-tetrahydro-1H-cyclopropa [c] quinoline (3).
2-Acetyl-3-hydroxymaleimide derivatives (1a, b) reacted with various amines to give the corresponding anilino and hydrazino derivatives, and heterocyclic compounds such as pyrazoles, pyrrolidino [3, 4-c] pyrazoles, and pyrrolidino [3, 4-e] [1, 4] diazepines.
Liberation of ethylenediamine and crystal water from aminophylline JP was examined by differential thermal balance and X-ray diffraction methods. Differential thermal balance analysis of aminophylline, carried out in air, at the temperature elevation rate of 2.5°/min, showed that loss in weight started at around 67°, accompanied with endothermic peak which transited to a small endothermic peak, and the thermal change ended at around 130°when weight loss was completed. The thermal balance curve also showed changes corresponding to the two endothermic peaks. Samples were collected at various decomposition rates for analysis and it was found that there may be two routes of decomposition ; one in which aminophylline would lose ethylenediamine and crystal water and convert directly into anhydrous theophylline, and the other in which it loses a part of crystal water to change into aminophylline with about one-half molecule of crystal water (tentatively termed α-aminophylline) and then change into anhydrous theophylline. It was considered that the first endothermic peak corresponds to the overlapping of the process of conversion of aminophylline directly into anhydrous theophylline and the process of aminophylline changing into α-aminophylline, and the second endothermic peak corresponds to the process of liberation of ethylenediamine and crystal water from α-aminophylline.
The graphic programs (QSAR), which are used for selection of compounds on the basis of a regression equation in the Hansch and de novo analysis, were developed. The flows of the programs are controlled by function-key and alphabetical-numericalkey operations. They can display perspective molecular figures based on atomic coordinates and calculated biological potencies of analogs on CRT. At present, 283 kinds of substituent data are available from the data-file, where eight kinds of physicochemical parameters and constituent atomic coordinates are stored for each substituent. Two examples, that is, the Hansch analysis of barbituric acid derivatives and de nove analysis of antipyrine derivatives, are shown to explain the outline. These are useful tools for quantitative drug design studies.
Absorption of indomethacin from the rabbit rectum was examined in comparison with the suppositories containing indomethacin polymorphs (α- or γ-form). Rectal suppositories were made with Witepsol H12. Plasma levels of α-form indomethacin was higher than that of γ-form. The commercial product (Inteban suppository) made with polyethylene glycol (PEG) base was also examined. Plasma level of Inteban was similar to that of α-form. The relationship between the thermodynamic activities of indomethacin polymorphs and their rectal absorption was discussed.
Deposition of plasma-polymerized ethylene film on a glass substrate loaded in a bell-jar type plasma apparatus was examined by varying plasma parameters such as high frequency power, monomer flow rate, and location of the substrate. Variation of high frequency power resulted in a fairly small change of the deposition rate of the polymer film, presumably because of an external electrode system employed for plasma break down of argon entering from the upper side of the bell jar. Effective transparency of the film having 10000 Å thickness was obtained throughout the visible light range while enhanced light absorbance was observed with shorter wavelengths in the ultraviolet range so that it is possible to estimate the film thickness by simply measuring absorbance of the polymer deposited on a quartz glass slide at 300 nm. An increase of ethylene flow rate resulted in higher deposition rate, but an abrupt drop in the deposition rate was experienced under flow rate exceeding a certain limit, while and adhesion of powder material was observed at the same time. Varying height of the sample stand on which the substrate was placed also affected the deposition rate but the optimum height could be found from the uniform film thickness throughout the surface of the glass slide. Deposition rate at various locations other than on the sample stand also differed greatly but a gas chromatographic study revealed a considerably uniform ethylene concentration within the bell jar so that it was assumed that the mode of polymer deposition in a given apparatus was mainly derived from the gas discharge condition at the surface of the substrate.
The metabolism of clofluperol by liver microsomes from both male and female Wistar rats was studied using 3H-labelled clofluperol. p-Fluoro-o-tritiobenzoylpropionic acid was the only radioactive metabolite formed from the microsomal metabolism of 3H-clofluperol. The apparent Vmax value for its metabolism by the liver microsomes of male rats was two times greater than that by female rats, while such difference was not shown in the apparent Km value. The effect of castration and pretreatment with SKF 525-A on the distribution of 3H in the blood, brain, liver, adrenal, and pancreas of male rats was studied after dosing 3H-clofluperol (0.3 mg/kg) orally. Concentration of 3H in the blood and adrenal of castrated male rats and those in all tissues examined of SKF 525-A-pretreated male rats were generally higher than those in the corresponding tissues of intact male rats. These results suggest that clofluperol ingested is first N-dealkylated by the microsomal drug-metabolizing enzyme of the liver, and the sex difference observed in the disposition of clofluperol may depend on the extent of its metabolism in the liver.
Effect of phenytoin on the membrane potential of skeletal muscle was compared between the genetically dystrophic mice and ouabain-treated mice, and the following results were obtained. 1) The resting membrane potentials of both dystrophic and ouabain-treated mice were lower than that of normal mouse (-75.1 mV). After phenytoin administration, the resting membrane potential of dystrophic mice recovered to the level of normal mice (from -69.3 to -73.6 mV) but that of ouabain-treated mice did not (from -69.6 to -70.0 mV). 2) The maximum rate of rise of action potential from both dystrophic and ouabaintreated mice was equally lower than that from normal mouse. Afte phenytoin administration, it recovered to the level of normal mouse in the dystrophic mice but not in the ouabain-treated mice. These results suggest that the stimulation of Na+ pump is not likely to be the primary cause of the recovery of membrane potential by phenytoin in the genetically dystrophic mice.
A method for the rapid estimation of paeoniflorin in crude drugs of paeony root was established by the use of a high-speed liquid chromatography. Paeoniflorin is separated by a 25 cm column of Zorbax CN, using liquid chromatograph of Shimadzu-Du Pont Model LC-2, with 0.1 M HClO4 (pH 3.5)-CH3CN (9 : 1, v/v) as the desorption solution, and the separation is completed within 10 min. Paeoniflorin is the crude drugs is extracted with water and the aqueous extract is injected into the column. The content of paeoniflorin was calculated from the calibration curve previously prepared using a standard. Precision of the determination is about±1% and detection limit is 15 ng (S/N ratio, 3). This method is considered to be useful for the evaluation of paeony root.
A method was established for the quantitative determination of furazolidone in chicken tissues by high-performance liquid chromatography (HPLC). An ethyl acetate extract of the sample was purified by alumina column chromatography with carbon tetrachloride-isopropanol (1 : 1, v/v) as an eluate. The solvent was evaporated and the residue was dissolved in methanol-water (95 : 5, v/v) containing o-nitrophenol as an internal standard. An aliquot of the solution was injected into Hitachi gel #3011 column. Furazolidone was separated from other substances by using methanol-water (95 : 5, v/v) as a mobile phase. Recovery of furazolidone from the muscle and liver added with it in levels of 0.01 to 0.1 ppm was 68.9% and 68.5%, respectively.
X-Ray analysis of a single crystal of 1-benzyl-5-ethyl-1, 2, 5, 6-tetrahydro-2-oxo-4-pyridineacetic acid (1) has confirmed the location of the C=C bond, planarity of the α, β-unsaturated δ-valerolactam ring, and an axial-like conformation of the ethyl group at the 5-position, which were recently proposed on the basis of chemical and spectroscopic evidence. The carboxylic hydroxyl group and the lactam carbonyl group in the molecule examined respectively form hydrogen bonds with the lactam carbonyl and the carboxyl group of another molecule, producing a cyclic dimer.