A reaction from various kinds of nitroquinoline with hydroxylamine in potassium hydroxide alkalinity produced a novel product, furazanoquinoline, besides the known amino derivatives. The products obtained were furazano [3,4-f] quinoline (5) from 5-nitroquinoline (1) and 6-nitroquinoline (6), and furazano [3,4-h] quinoline (10) from 7-nitroquinoline (8) and 8-nitroquinoline (11). The reaction mechanism was believed to be as shown in Figs. 2 and 3. The photoreaction of benzofuroxan (19) in acetonitrile containing a little water, under a high pressure mercury lamp, produced 1H-azepine-2,7-dione (20), while under irradiation using a low pressure lamp, 6H-furazano [4,5-c] carbazole-3-oxide (21) and compound 20 were obtained. Then the photoproduct 20 produced photodimer 22 by irradiation in acetonitrile: water (9:1, v/v) using a high or low pressure mercury lamp, while photolysis with alkali proceeded as in the photoreaction of N-alkylimide to give 7-hydroxy-1H-azepine-2-one (23). When pyrido [2,3-c] furoxan (24) was irradiated in acetonitrile containing a little water with a low pressure mercury lamp, 3-nitro-2-pyridone (25) was obtained. When compound 24 was irradiated in the presence of morpholine with a low pressure mercury lamp in an argon atmosphere, 6-morpholinopyridine 2,3-dioxime (26) was produced. Quinoxaline 1,4-dioxyde derivatives (31, 33), phenazine 5, 10-dioxide derivatives (36, 37) and pyrido [2,3-b] pyrazine derivatives (38, 39) were synthesized from the corresponding furoxan catalyzed by silica gel or molecular sieves, and their antibacterial properties were evaluated. The results of antibacterial screening tests in vitro, revealed strong activity against Bacteroides fragilis.
In recent years, organic reactions in aqueous media have attracted much attention, not only because these reactions eliminate the necessity of vigorous drying of solvents and substrates, but also because unique reactivity and selectivity are often observed in the aqueous reactions. Furthermore, organic reactions in water may lead to the development of environmentally friendly chemical processes. We have now developed various types of catalytic organic reactions in aqueous media. Catalytic asymmetric aldol reactions in aqueous media have attained by using rare earth metal triflates and a chiral multi-dentate ligand. Lewis acid catalysis has become feasible in water by using combinations of water-compatible Lewis acidic cations and anionic surfactants. These new catalysts were found to form stable colloidal dispersions and catalyze various reactions in water. Moreover, Brønsted acid- and palladium-catalyzed reactions in water have also been performed with the aid of surfactants.
It has been established that ionic surfactants, whether cationic or anionic, provide crystalline molecular complexes stably with various aromatic compounds as additives. Among various additives phenolic compounds are especially favorable for both surfactant species. Other than these additives, cationic surfactants easily provide crystalline molecular complexes with basic materials and even with non-polar substances such as biphenyl and phenanthrene. The isolated surfactant molecular complexes were analyzed by X-ray. To date the number of the obtained surfactant molecular complexes exceeds two hundred species or more and thirty or more of them were structurally analyzed. These surfactant molecular complexes were shown to be novel surfactant species different from their mother species, supplied with enhanced solubility to the complex additives. We applied these characteristics to sparingly water soluble drugs as the complex additive to modify them into easily water soluble drugs. The obtained complex drugs revealed an improved behavior in solubility and dissolution rate compared with pure drugs.
Asp-hemolysin is a cytolytic toxin that is produced by Aspergillus fumigatus. This toxin is lytic for erythrocytes of humans, rabbits and sheep. However, Asp-hemolysin is inactived by the addition of serum or blood plasma. This study was undertaken to identify plasma components inhibitory to the hemolytic activity of Asp-hemolysin. α2-Macroglobulin (α2M) was isolated from the human blood plasma by affinity chromatography on a column containing Asp-hemolysin coupled to Sepharose. However, the hemolytic activity was only partially inhibited by α2M. Apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoprotein (LDL), inhibit the activity of this hemolytic toxin. When 20 μg apoB was added, the hemolytic activity was almost completely inhibited. Furthermore, similar inhibition was observed in the filtrates separated from the incubation mixture of Asp-hemolysin with LDL or apoB following ultrafiltration through a membrane with a molecular mass cutoff of 100000. These results suggest that the inhibition by LDL is due to apoB binding to Asp-hemolysin. The binding activity of LDL to Asp-hemolysin was measured. LDL binds to Asp-hemolysin with an affinity as high as the LDL receptor. The apparent Kd, determined by Scatchard plot analysis, was 8.9 × 10-9M 125I-LDL. Oxidized LDL (Ox-LDL), but not acetylated LDL, inhibited the hemolytic activity of this toxin. The inhibitory effects of Ox-LDL increased with the time of Cu2+-induced LDL oxidation. Similar inhibition was observed in the filtrate separated from the incubation mixture of Asp-hemolysin with Ox-LDL (for 2 h of oxidation) following ultrafiltration through a membrane with a molecular mass cutoff of 100000. However, at longer LDL oxidation times, the inhibition by the filtrates was less than the control mixture without ultrafiltration. These results suggest that the inhibition of the hemolytic activity by Ox-LDL was due to the binding of Ox-LDL to Asp-hemolysin at short LDL oxidation times.
Two formulations of 0.5% vancomycin hydrochloride (VM) eye drops (VM-B and VM-C eye drops) were prepared by dissolving commercial VM powder for injection with preserved water B (PWB) containing phosphate buffer and preserved water C (PWC) containing only antimicrobial preservative, respectively. The VM-B eye drops have neutral pH (about 6.3), and the VM-C eye drops acidic pH of about 3.5. The pharmaceutical examination of these eye drops was performed regarding its clinical application to MRSA eye infection. In an irritability test using a rabbit’s eye, the average number of winks after instillation of one drop of VM-B eye drops was 0.8 times/min and significantly smaller than that of VM-C eye drops (2.0 times/min). In dark storage at 4°C, no change of VM concentration in both eye drops was observed for 25 weeks after preparation and the mean residual concentrations as determined by the HPLC-UV (240 nm) method were constant over 90% for 8 weeks, of the initial oncentration. However, the residual VM concentration of VM-B eye drops under a room condition declined to 58% after 4 weeks and 20% after 8 weeks, and VM in light storage at 40°C was not detectable after 8 weeks. The drug concentration of VM-C eyey drops declined to 83% after 4 weeks and 74% after 8 weeks under a room condition, and to 46% after 4 weeks and 20% after 8 weeks under light storage at 40°C. Under these storage conditions, the precipitation of VM related crystals was observed in both the eye drops when the residual percentage of VM was lower than 80%. Judging from HPLC chromatograms of a solution of the precipitated crystals, it was suggested that this crystal was degradation products of VM. The VM-B eye drops was applied to a patient with MRSA eye infection, because other medication was not effective. After continuous instillation of a drop per times every hour to both eyes, MRSA in corneal culture turned out negative after one week, and the clinical condition was remarkably improved. On the basis of the result of eye-irritability, VM-B eye drops with neutral pH was suggested to be superior to acidic VM-C eye drops from a safety point of view. It was also indicated that VM-B eye drops can be effectively used for 8 weeks under dark storage at 4°C for MRSA eye infection, which is a useful piece information for the proper usage of the VM eye drops.
A novel ointment base suitable for the treatment of bedsore at the recovery stage was developed by the use of hydroxypropyl methylcellulose (HM-HPMC) modified on the basis of the hydrophobicity. A considerable sustained release of drug (minocycline hydrochloride) formulated to the ointment (T50 of 170 min) was attained with a macrogol ointment (MO) mixed with the HM-HPMC and Carbopol (CP) of the formulating ratio of 3:7. It was also found that a change in the formulating ratio of HM-HPMC and CP lead to a change in the drug release rate. The water absorption property of the ointment base, required to absorb on exudative solution in applying to the bedsore treatment, was as high as that of an ointment base containing hydroxypropyl cellulose (HPC) and CP reported in our previous paper. We clinically evaluated the effectiveness of the bedsore treatment, in which different ointment bases were applied to patients at different stages of the bedsore. A total of 22 cases were divided into two categories for applying to the different treatments. One category comprised of 11 subjects was treated with a povidone-iodine sugargel, which was the conventional method in our hospital, while the other 11 subjects were treated by the use of the newly developed ointment bases in consideration for the different stages of the bedsore. In comparison of the clinical results with the healing index, we ascertained that the latter method was significantly more efficacious (p<0.01-0.05) than the conventional one. The effectiveness was emphasized in treating the intractable bedsore classified into the grades IV and V. Therefore, we confirmed that the newly developed ointment base formulation is useful in treating bedsore at each stage.
As reported previously (Kosuge et al., Yakugaku Zasshi, 120, 408 (2000)), methyl gallate, a gallic acid derivative, which has been one of compounds isolated from extracts of Psidium geneus Myrtaceae, selectively suppresses Th2 cytokine secretion. In the present study, to examine more effective compounds than methyl gallate, the effects of various gallic acid derivatives on the secretion of helper T cell subtype specific cytokines from anti CD3-stimulated spleen cells were investigated. Ten μg/ml of methyl gallate and ethyl gallate remarkably suppressed the secretion of IL-4 and IL-5, Th2 cytokines, but did not suppress meaningfully the secretion of IFN-γ, a Th1 cytokine. On the other hand, the other gallic acid derivatives suppressed the secretion of both IL-4 and IFN-γ. Ten μg/ml of methyl gallate suppressed the secretion of IL-2, a Th1 cytokine, but the same concentration of ethyl gallate did not suppress it. In conclusion, it seemed that ethyl gallate was the most selective inhibitor for the secretion of Th2 cytokines among gallic acid derivatives used in this study.