The investigation on the constituents of five Apocynaceae plants including Nerium odorum (and N. oleander), Cerbera Manghas, Anodendron affine, Trachelospermum asiaticum, and Allamanda neriifolia were described. Novel cardenolide glycosides, pregnanes, and iridoids were isolated and their structures were determined. The distribution of the cardenolide glycosides in the wild and cultivated strains of Nerium were examined quantitatively. The biogenetic relationships of the new substances to the known components and chemotaxonomy of the plants were also discussed.
New reactions developed for the synthesis of medicinally useful trifluoromethyl compounds are discussed. First, the trifluoromethylation of aromatic halogen compounds with CF3I and Cu powder is presented. This method is applicable to a wide range of aromatic halides, while aliphatic halides cannot be converted to trifluoromethyl compounds. This difficulty was removed by two-step procedure. CF3I and Cu powder were shaken in a stainless steel tube, and the excess of Cu powder was removed by filtration. The solution of [CF3-Cu] was treated with halogen compounds to give trifluoromethyl compounds. Next, the Friedel-Crafts reaction of trifluoropropene was presented, which gave trifluoropropyl compounds. It was very difficult to obtain these products by other routes. Attempted application of the trifluoropropyl compounds are included. Finally, some reactions useful for the synthesis of special types of trifluoromethyl compounds were summarized, where photoreaction, 1, 3-dipolar reaction, and ene reaction of trifluoromethyl compounds are included.
Isatin reacts in the presence of pyridine with acetic anhydride to give spiro-dimers, 1 and 2. The former was converted with acid to 2. Treatment of 2 with diazomethane yielded methylester (3) which was converted with the excess reagent to cyclopropane derivative 4. Compound 1 was heated under reflux in methanol to yield 5, 6-dihydrobenz [c, d] indolinone (5) (46.6%) together with a little 6, 7, and 8. On treatment with anilines or hydrazine, 1 was converted to anilides or 2, 3-dihydro-4, 4-phthalazinone derivative.
In order to examine the relationship between the biological activities and structural variations of xanthine derivatives, several 1-aminoxanthines were synthesized from 1-methylxanthines and their cardiac activities were examined. Xanthine derivatives, such as caffeine, theobromine, 7-ethyltheophylline, 7-allyltheophylline, proxyphylline, and diprophylline were allowed to react with hydrazine hydrate to give 1-aminoxanthines and the following biological testings were carried out : (a) phosphodiesterase inhibition (b) activities on guinea-pig papillary muscle (c) activities on guinea-pig atrium (d) activities on guineapig tracheal muscle. The cardiac activities of 1-aminoxanthines were weaker than those of theophylline.
Two flavanones, kushenol E (I) and kushenol F (II), one flavonol, kushenol G (III), and two flavanonol, kushenol H (IV) and kushenol I (V) were isolated from the dry roots of Sophora flavescens AIT. (Leguminosae). Their structures were elucidated on the basis of spectral data especially 1H-nuclear magnetic resonance spectra and 13C-nuclear magnetic resonance spectra. Kushenol F (II) having a lavandulyl group at C-6 was first isolated from this source.
Two γ-hydroxybutenolide derivatives, 1, C26H30O9, mp 262-263°C (dec.), [α]25D-7.4°, and 2, C26H30O10, mp 285-286°C (dec.), [α]25D-127.0°, have been isolated from the bark of Phellodendron amurense RUPRECHT (Rutaceae). The structures of these compounds have been determined by spectral analyses and partial syntheses from their parent limonoids.
The effects of staphylococcal phage lysate (SPL) on polyclonal antibody secretion, and mitogenic activity of mice spleen cells were studied. 1) SPL, at a concentration of 30 μl/ml augmented mitogenic activity 1.9 times in mouse spleen cell cultures, however no enhancement of mitogenic activity was observed in B cell depleted, T cell cultures and in athymic nude mouse spleen cell cultures. 2) Augmentation of polyclonal antibody secretion by SPL was observed in athymic nude mouse spleen cell cultures, and did not enhance depleted of macrophages, by passage through Sephadex G-10. 3) By injection of 100 μl SPL, in vivo adjuvant activity against sheep red blood cells were augmented 2.4 times. As revealed above, SPL enhance both mitogenic activity and polyclonal antibody secretion of mouse spleen cells, but augmentation of mitogenic activity is not observed by SPL in T cell, or B cell cultures alone, existence of both T cell and B cell is required to mitogenic activity by SPL. Augmentation of polyclonal antibody secretion by SPL needs B cell, T cell and macrophages.
To evaluate the bactericidal activity of antiseptics against many different strains, we devised a modified phenol coefficient method by using microtitration plates based on that of the Association of Analytical chemists, and counted survivors to find the shortest contact time for various concentrations at which almost all bacteria were killed. Benzalkonium chloride (BAC) was bactericidal against all 242 strains tested at 500 μg/ml in 10 min of contact at 25°C. Under the same conditions, chlorhexidine gluconate (CHG) was bactericidal against 90% even at 1000 μg/ml. Among these strains resistant to 1000 μg/ml, Pseudomonas, Serratia, and Proteus species comprised 45% of the strains. The killing rate of BAC was fast, but the bactericidal activity of CHG with short contact time was weaker than its bacteriostatic activity for 24 h. The bactericidal concentration of BAC and CHG for 30 s of contact at 25°C was 500-5000 μg/ml and 5000-30000 μg/ml in a 10% solution of human serum, and 2500->10000 μg/ml and 10000->40000 μg/ml in a suspension of 2.5% dried yeast, respectively. The 10% human serum stimulated the bactericidal activities of BAC and CHG slightly against some test bacteria.
Release mechanisms of theophylline from newly designed sustained release granules and tablet which contains sustained release granules have been studied by dissolution tests and observation of scanning electron photomicrographs. Sustained release granules have been prepared from plain granules by coating with water-insoluble materials. Dissolution profiles showed that approximately 90% of the drug was released in 8 h from granules and tablet, indicating that both preparations prolonged release of the drug. By comparison of several release kinetic theories, it was suggested that the release rate of the drug from these preparations was mainly dependent on the rate of drug diffusion through the membrane. The mean cumulative absorption profile after administration of sustained release granules to four healthy volunteers was very similar to the release profiles from the granules. Therefore it may be expected that absorption of the drug was affected slightly by ingestion of food and changes in gastrointestinal motility, gastric emptying rate and pH in the gastrointestinal tract.
The possibility of metabolism of dantrolene sodium with fresh stool was investigated because a low correlation was observed between dantrolene sodium dose and its serum concentrations. After combination of dantrolene with sterilized broth (pH 7.1) or 8% sterilized stool culture (pH 5.6) without further anaerobic precautions, dantrolene did not degrade in the incubation mixture. This indicate that dantrolene dose not react with the components of broth and stool cultures, and that it is stable at these pH values. On the other hand, after combination of dantrolene with 1% or 8% human faecal contents in a broth, the drug disappeared rapidly in the incubation mixture in proportion to stool concentration. The degradation of dantrolene was followed by a high performance liquid chromatography (HPLC) and the appearance of a metabolite was followed by HPLC and thin-layer chromatography (TLC). The metabolite was identified to be 7-aminodantrolene by HPLC and TLC.
The methamphetamine-induced stereotypy of mice in a three-dimensional open field divided into nine unit spaces was visually observed. Each space was a little larger in size than the mice. The resultant positional behaviors were analyzed by use of four measures, namely, total frequency of visits to unit spaces (N), spacial distribution of the animal location (H1) obtained by the equation H1=-Σ__ipilog2pi (bits), where pi was the frequency of visits to a unit space numbered as i/N, approximated visit direction (HII) obtained by the equation HII=-Σ__(i, j)pipijlog2pij (bits), where pij was the frequency of visits from the i unit space to a unit space numbered as j/frequency of visits to the i unit space, and visit direction from the 6th unit space (H6→) obtained by the equation H6→=-Σ__jp6jlog2p6j (bits), where p6j was the frequency of visits from the 6th unit space to the j unit space/frequency of visits to the 6th unit space. By increasing N methamphetamine gave and maximum effect at 2-4 mg/kg, s.c., but dose-dependently reduced the entropies, that is, HI, HII and H6→. Haloperidol (0.1-1 mg/kg, p.o.), metoclopramide (1-10 mg/kg, p.o), chlorpromazine (3-30 mg/kg, p.o.) and sulpiride (1-100 mg/kg, i.p.) dose-dependently antagonized the methamphetamine (8 mg/kg, s.c.)-induced stereotypy. These results suggest that the present method is useful for the analysis of stereotypy and a better understanding of pharmacological activities of antipsychotic drugs.
The present study was undertaken to determine if adenosine triphosphate-magnesium chloride (ATP-MgCl2) would have beneficial effects on the membrane electrolytes transport and deformability of shocked red blood cells (RBC) with impaired cellular energy metabolism. Shocked RBC suspensions were obtained by incubation of 10% rabbit RBC suspension in phosphate buffered saline at 37°C for 14 h. Cellular ATP level was reduced to approximately 6% of normal value by this incubation. ATP-MgCl2 (100 μM), added to the incubation medium along with glucose (10 mM) after 14 h of incubation, significantly prevented further decreases in cellular ATP and 2, 3-diphosphoglycerate (2, 3-DPG) levels. Increases in intracellular sodium concentration and potassium leakage from RBC were counteracted by simultaneous ATP-MgCl2 and glucose treatment and pH of the incubation medium showed significant reduction compared with the control. It was also observed that glucose utility and deformability of shocked RBC were improved by ATP-MgCl2 and glucose treatment. These results indicate that ATP-MgCl2 would be helpful to restore the impaired RBC function by improving the intracellular energy metabolism.
Preliminary examination of antitumor screening with Ehrlich ascites carcinoma and HeLa cells was carried out on the extracts prepared from 91 species of Chinese herbs which are said to be effective for tumor in China, in cooperation with the Institute of Chinese Materia Medica in Academy of Traditional Chinese Medichine.
The difference was examined in the nature of judgment drawn by the test of hypothesis, interval estimation, and Bayesian analysis with the same set of data obtained in a balanced two-period crossover bioequivalence trial. The conventional method and the method of Westlake, in which and interval symmetric with respect to the mean of the standard preparation was calculated, were used to estimate 95% confidence intervals. As to the Bayesian analysis, two different methods of calculation were employed. The bioequivalent region of the coefficient of intrasubject error variation, the ratio of the square root of the intrasubject error variance to the mean of bioavailability parameter for the standard preparation, was calculated against the ratio of the means for the test and standard preparations by using these methods. The region accepted as being bioequivalent based on the Westlake method was slightly larger than that based on the conventional method and agreed with that obtained by one method of calculation based on the Bayesian analysis.