In order to examine the effect of α- and β-cyclodextrin on the intestinal absorption of barbituric acid derivatives (BA), some in vitro experiments were carried out by the use of everted rat small intestine, and it was found that the absorption depended on the concentration of BA in mucosal solution. Cyclodextrins were useful for increasing the solubility of BA and hardly interfered with permeation of BA through the everted rat small intestine. The highest concentration of BA was available in α-cyclodextrin solution, but by comparison in the same amount, β-cyclodextrin was more effective than α-cyclodextrin on increasing the solubility of BA. Complexes of β-cyclodextrin and BA were prepared, and BA absorption from each complex solution was compared with that from the corresponding BA solution. The absorption of BA from complex solution exceeded that from BA solution, since the complex is more soluble than BA itself. Blood levels in rabbits after oral administration of BA and its β-cyclodextrin complexes were compared, and its results indicated that the solubility difference between BA and its complexes has an effect on the bioavailability of BA.
Examinations were made on the following reactions for the synthesis of 2-substituted furo [2, 3-b] quinoxaline (I) : (a) Application of alkali to 1-(3-chloro-2-quinoxalinyl)-2-alkanone (IV) in dioxane, (b) refluxing of 1-(3, 4-dihydro-3-oxo-2-quinoxalinyl)-2-alkanone (V) in acetic anhydride, in the presence of conc. sulfuric acid, (c) heating of V with polyphosphoric acid, and (d) application of phosphoryl chloride to IV or V. It was found that method (c) was the best and that 2-chloro-3-(2-chloro-1-alkenyl) quinoxaline (VIII) is the main product obtained by method (d). 2-Substituted 1-phenylpyrrolo [2, 3-b] quinoxaline (II) is obtained by heating IV with aniline, and 2-substituted pyrrolo [2, 3-b] quinoxaline (III) is obtained by the application of sodium amide to 1-(3-methoxy-2-quinoxalinyl)-2-alkanone (X), in the presence of methyl ethyl ketone.
5-Alkoxy-3-(N-substituted carbamoyl)-1-substituted phenylpyrazoles (VIII) were synthesized from 5-hydroxypyrazole (IV) by alkylation and amidation. The relationship between their structures and biological activities, such as analgesic or antiinflammatory activities, was assayed by the carrageenin foot edema method and the acetic acid stretching method. Among these compound, 1-(m-chlorophenyl)-3-(N, N-dimethylcarbamoyl)-5-methoxypyrazole (VIII-15) had the most potent analgesic and antiinflammatory activities.
Reaction of 2-cyano-4-methoxy-6-methyl- (I), 4-cyano-6-methoxy-2-methyl- (II), 5-cyano-4-methoxy-2-methyl- (III), and 5-cyano-4, 6-dimethoxy-2-methylpyrimidine (IV) with Grignard reagents is described. While 2-cyano and 4-cyano derivatives (I, II) were transformed to the corresponding pyrimidinyl ketones as expected, 5-cyano derivatives (III, IV) were converted to the addition products, 5-cyano-6-ethyl-1, 6-dihydro-4-methoxy-2-methyl- (VIIa) and 5-cyano-2-ethyl-1, 2-dihydro-4, 6-dimethoxy-2-methylpyrimidine (XI), respectively.
In recent years there have been numerous reports about N2-acetyl-L-glutamine aluminum complex (KW-110) which has been evaluated as an anti-ulcer drug, especially as a gastric mucous membrane protective one. In order to elucidate the characteristic of this drug, the interaction of various aluminum compounds, such as aluminum chloride, aluminum potassium sulfate and KW-110, with chondroitin sulfate A, one of the most important components of gastric mucous membrane, was investigated by the equilibrium dialysis method in aqueous solutions at 37° and 22°. The result are as follows ; there are two binding sites on chondroitin sulfate A for aluminum of KW-110. One has about 1.5 binding sites of relatively strong affinity (ΔF1=-6 kcal/mol). The other has about 3.5 binding sites of relatively weak affinity (ΔF2=-3 kcal/mol). On the other hand, there is only one binding sites on chondroitin sulfate A for aluminum ions of inorganic aluminum compounds. In the latter case, the binding sites on chondroitin sulfate A correspond to the first one for KW-110, and this kind of binding is due to the electrostatic force. Therefore it is assumed that the second one for KW-110 is characteristic of aluminum derived from KW-110.
Drug interactions of aspirin with chlormezanone on analgesic and anti-inflammatory activities, acute toxicity, and distribution of aspirin were studied by oral administration of combined drugs to mice and rats. (1) Analgesic activity against pressure stimuli and acetic acid-induced writhing in mice was potentiated by combined use of both drugs. Combined effect of both drugs on anti-inflammatory activity against carrageenan-induced edema in rats was additive in all of combination ratios tested. In addition, chlormezanone alone was found to be ineffective for inhibition of chronic inflammations in rats. Acute toxicity in mice was antagonistically reduced by combined use of both drugs. (2) Analgesic activity and acute toxicity showed no significant difference among combinations in various weight ratios of both drugs, but anti-inflammatory activity was the most powerful in the combination of aspirin to chlormezanone of 4 : 1. (3) When combined drug (aspirin to chlormezanone=4 : 1) was administered to mice with acetic acid-induced writhing, chlermezanone increased significantly the concentration of aspirin into the tissues, including the inflamed tissue. These results suggest that the combination of aspirin with chlormezanone induces favorable effects in their pharmacological actions and potentiated analgesia is related to alterations in the distribution of aspirin by combined use of chlormezanone.
Callus cultures derived from haploid embryoids formed in the cultured anthers of Datura innoxia and the plants regenerated from these callus tissues were examined for variations in the chromosome number and the alkaloid composition. Most of the plants regenerated from callus cultures were found to be diploid as a result of spontaneous chromosome doubling presumably occurred during subculturing. In addition to diploids, a small number of haploid as well as tetraploid plants were obtained. Although the alkaloid contents of these callus tissues were generally low, two of the cultured strains maintained relatively high contents during successive subculturings over 3 years. The average alkaloid content of the regenerated plants was similar to that of normal plants. Although in one culture strain many regenerated plants showing a higher alkaloid content (ca. 1%) were obtained, this characteristic was not transmitted to the progeny plants. Some of these regenerated plants were abnormal because they produced no detectable amount of scopolamine or hyoscyamine. Among these abnormal plants, one group contained a considerable amount of scopolines and scopines and another group contained aposcopolamine. Breeding tests showed that the abnormal traits were transmitted to some of the self-pollinated progeny plants (S1), but the abnormal alkaloid patterns disappeared completely in the subsequent generation (S2). These results suggest that variations in the alkaloid composition found in the plants regenerated from callus tissues are not due to genetic mutations but due to Dauermodification, considered as a temporary cytoplasmic inheritance induced in cultured cells by enviromental conditions.
Reaction of 4-aminoquinoline 1-oxide (4-AQO) with 4-chloroquinoline (4-ClQ), was examined in order to compare the reactivity of 4-hydroxyaminoquinoline 1-oxide (4-HAQO) with that of 4-AQO to reactive aryl halides. Reaction of 4-AQO with 4-ClQ afforded 3, 3'-(4-amino-4'-hydroxy) biquinoline (1), 4-aminoquinoline (3), and 4-hydroxyquinoline (4). A reaction mechanism for the formation of the biquinolines was also discussed.
A new acid amide was isolated from the dried fruits of Capsicum annuum L. and its chemical structure was determined as N-(13-methyltetradecyl) acetamide (I) from chemical and spectral data. I was further synthesized from 7-methyloctanoic acid.
Dissolution rates of various tablets and powder with various particle size distribution were measured by using the rotary basket method adopted in USP XIX (1975). Simulation technique using a computer can be applied to the dissolution measurement of these samples, the amount of solute dissolved was calculated step by step on the basis of the Nernst-Brunner's dissolution model, and a good agreement was found between the calculated and experimental amount of dissolution for various tablets and powder. The tablet was handled as an iso-volume sphere, poly-dispersed powder was handled as a gathering of mono-dispersed sphere, and the observed dissolution rate constant (k (obs.)) agreed well with the dissolution rate constant (k (simu.)) obtained by the simulation technique. The effect of tablet size, initial solute concentration in the dissolution medium, and the rotating speed on the dissolution rate constant (k (simu.)) or dissolution rate was tested. k (simu.) decreased with an increase in tablet size, dissolution rate decreased with an increase in initial solute concentration, and k (simu.) increased linearly with an increase in rotating speed. The proposed theory and simulation technique are useful for the analysis of the dissolution of tablets or powder with various particle size distribution.
Diffusion coefficients and dissolution rate constants of Sudan III (model compound) in a gelatinous ointment base prepared from polyethylene, hydrated vegetable oil, and liquid petrolatum were measured by using a drug-release cell. Simulation technique using a computer can be applied to the measurement of diffusion and dissolution of Sudan III in a semi-solid material, the release percentage in the liquid phase was calculated step by step on the basis of the proposed model, and a good agreement was found between the calculated and experimental release percentages for various ointment bases. Poly-dispersed powder was handled as a gathering of mono-dispersed sphere and the theoretically resonable results were obtained from the model calculation that smaller particles dissolve faster than larger particles and that dissolution rate of particles affects the release percentage. Diffusion coefficient and dissolution rate constant, which is a constant under a stationary state, were inversely proportional to the viscosity of liquid component in an ointment base. The proposed theory and simulation technique are useful for the analysis of the diffusion of drugs and dissolution of a drug powder in an ointment base.
Drug release from the O/W emulsion was measured by using a drug-release cell. Sample emulsion was prepared by vigorous mixing of a mixture of water, isopropyl myristate, surface-active agent (PBC-31, Nikkol), and salicylic acid (model compound), and the droplet size distribution of sample emulsion was measured by a particle size analyzer (Japan Regulator Co.). The effect of the amount of a surfactant on the release percentage in the liquid phase was tested by changing its amount from 0.2 to 2%. Simulation technique using a computer can be applied to the measurement of drug penetration at the droplet surface, release percentage in the liquid phase was calculated step by step on the basis of the proposed model, and a good agreement was found between the calculated and experimental release-percentages at the measured points with various lapsed time. Poly-dispersed droplets were handled as a gathering of monodispersed sphere, drug migration in the droplet was handled as the radial diffusion, and theoretically reasonable results were obtained from the model calculation that the drug release from the smaller droplet is faster than from larger droplets and the concentration in droplets near the surface is lower than that in the central part. The special resistance (X) of drug penetration at the droplet surface, which may be attributed to the presence of a surfactant film, was obtained and this resistance may be useful for the assessment of surfactants. The proposed theory and simulation technique are useful for the analysis of the drug-release from an emulsion or a cream.
Disintegration of erythromycin tablets was compared by the disintegration test method in Japanese Pharmacopoeiae VIII and by the Erweka Disintegration Tester, using commercial erythromycin tablets (200 mg/tablet) manufactured by 16 firms and marketed in Japan during June to September, 1975. From the result of these tests, four kinds of tablets that required the longest time for disintegration and a kind of standard tablet that required the shortest time were selected. These tablets were alloted to 20 female subjects at a time (making a total of 100 test subjects) by the Latin square design method. The subjects took the tablets before breakfast and serum level of erythromycin was measured by the bioassay method 2, 4, 6, 9, and 12 hr later to examine bioavailability in humans. According to its result, two of these five products were bioinequivalent and, especially, one of them showed a maximum serum level and AUC of only 4% and 3.8%, respectively, of the values obtained from the product giving the highest values. In order to find the reason for such bioinequivalence and to detect such a product, dissolution rate of these tablets was examined by four methods ; J.P. VIII, U.S. Pharmacopoeia XIX, Sartorius SS, and Erweka Tester. It was thereby found that one of the bioinequivalent products did not undergo disintegation or dissolution in a solution of below pH 6.5, and this was thought to be the reason for its poor absorption from the digestive tract. In the other product, dissolution at pH 5.0-5.5 seemed to be related to the serum level of the ingredient but this point requires further examinations.
Five quaternary ammonium salts administered orally did not influence the stomach emptying rate of phenol red. On the other hand, when these quaternary ammonium salts were administered subcutaneously, a retardation of stomach emptying rate was observed thirty minutes after oral administration of phenol red and its extent was given in the following order, isopropamide iodie>benzilonium bromide>benactyzine methobromide=anisotropine methobromide>propantheline bromide. The measurement of the stomach emptying rate may be practical and useful as one of the methods of screening tests for pharmacologic response, e.g., the anticholinergic effects of quaternary ammonium salts. Trichloroacetate administered subcutaneously did not cause a fall in the stomach emptying rate of phenol red but it accerelated the reducing effect of isopropamide iodide on the stomach emptying rate of phenol red.
Commercial stable isotope labeled compounds may have a high abundance of the corresponding radioisotopes, because of the simultaneous enrichment of the radioisotopes during the process for enrichment of the stable isotopes. The tritium or carbon-14 activity in commercial stable isotope labeled compounds was measured. The tritium activity in benzene-d6 and the carbon-14 activity in barium carbonate-13C were 42.5-360.4 pCi/ml benzene and 29.0 pCi/g carbon, respectively. These activities were extremely low compared with those in human body or daily diet. It is concluded that the radiations from the contaminated radioisotopes in stable isotope labeled drugs can cause no detectable health hazards, during short-term administration of drug to human subjects.
In continuation of previous studies on high-temperature fusion reaction of anthranilic acid (II) and primary amines to obtain 4 (3H)-quinazolinones in one step, o-toluidine was used as the amine and II was reacted with 4-picoline (Ia), in the presence of sulfur and 3-phenyl-2-(4-pyridyl)-4 (3H)-quinazoline (IIIa) was obtained with 2-(4-pyridyl)-3-(o-tolyl)-4 (3H)-quinazolinone (V). In order to clarify the formation of these products, Ia and II alone were reacted in the presence of sulfur and it was found that the use of two-fold moles of II resulted in the increased yield of IIIa but, at the same time, 2-(4-pyridyl)-benzothiazole (IVa) was formed. In order to elucidate this result, the same reaction was carried out with seven kinds of compound having an active methyl group.
Bovine plasma albumin inhibited the effects of hog insulin on the glucose uptake and the glycogen content of the mouse diaphragm muscle isolated, but did not affect the basal glucose uptake or the glycogen content of the diaphragm. Among these three kinds of albumin products used, no significant difference in their inhibitory effects was found. In the experiments on the inhibitory mechanism of albumin, the curve obtained with the plots of glucose uptake or glycogen content versus the concentration of glucose was neither hyperbolic nor sigmoidal.
The weight-average micellar weight of Aerosol OT in benzene and benzene-d6, M^^-H and M^^-D, were approximately determined by the sedimentation equilibrium method without the direct measurement of partial specific volume in both solvents, v^^-H and v^^-D, but with two assumptions, M^^-H=M^^-D and v^^-H=v^^-D. The weight-average association number, M^^-/molecular weight of Aerosol OT, was calculated to be 22 in both solvents.
A simple, one-step fractionation scheme was developed in order to improve currently used isolation techniques for synthetic chemical reactions. Therefore, tedious multi-step processes such as extractions, distillations, and recrystallizations can be excluded. Thin-layer chromatography (TLC) data, used for monitoring and optimizing a synthetic reaction, were directly extrapolated to high performance liquid chromatography (HPLC) system. Inorganic reagents, highly polar side products, and other strongly adsorbed components normally retained at the origin of TLC systems were removed by silica gel pre-column adsorption. Separation of less polar components was performed by HPLC using a solvent system previously selected by TLC examination. The desired products were rapidly fractionated from the crude reaction mixture. General applicability of this method was demonstrated by synthesizing various cholesterol derivatives according to the standard procedure described in Organic Syntheses.