This review highlights a recent study on allenic compounds by the author's group. In the first section, the organocopper-mediated ring-opening reaction of ethynylaziridines and palladium-catalyzed reductive synthesis of allenes are described. In the second section, palladium-catalyzed stereoselective cyclization of allenes, including the tandem reaction, leading to aziridines, pyrrolidines, benzoisoindoles, and cyclopropanes is presented. The final section reviews aziridination and medium-ring formation due to the intramolecular reaction of bromoallenes. The latter reaction is based on the author's recent discovery that bromoallenes can act as allylic dication equivalents in the presence of a palladium catalyst and alcohol.
There are many serious problems causing a food crisis such as desertification, population explosion, and environmental destruction, suggesting that a severe food crisis will become reality across the globe. Therefore, the transgenic plants, which have tolerance to environmental stresses, may take on greater and greater importance in attempts to increase food production. Aquatic photosynthetic organisms, such as prokaryotic cyanobacteria and eukaryotic green algae, are considered as an evolutionary origin of higher plants and their basic metabolisms including photosynthesis are similar to higher plants. Thereby, stress responsive genes or reactions from these organisms may be exceedingly advantageous sources for creation of stress-tolerant transgenic plants. In this study, the physiological roles and biosynthesis of abscisic acid (ABA), well known as a signal molecule in the adaptation to environmental stresses, in microalgae were investigated from the point of the view of its functional evolution in the response to environmental stresses. Chlamydomonas reinhardtii, a green alga, and Synechocystis sp. PCC 6803, a cyanobacterium, were employed in this study as model organisms. It is expected that this comparative analysis will provide basic information for the creation of stress-tolerant transgenic plants. ABA may act in C. reinhardtii as a signal molecule to induce antioxidant reactions for elimination of reactive oxygen species, but not to induce specific response reactions to mitigate water stresses. In Synechocystis, on the other hand, exogenously added ABA did not influence the growth and gene expression. Moreover, ABA did not relieve growth suppression caused by water and oxidative stresses. From the carotenoid composition and bioinformatic analysis, it can be suggested that the ABA biosynthetic pathway generally found in higher plants exists completely in C. reinhardtii, but incompletely in Synechocystis.
Wood creosote, the principal ingredient in Seirogan, has a long history as a known gastrointestinal microbicidal agent. When administered orally, the intraluminal concentration of wood creosote is not sufficiently high to achieve this microbicidal effect. Through further animal tests, we have shown that antimotility and antisecretory actions are the principal antidiarrheal effects of wood creosote. Wood creosote inhibits intestinal secretion induced by enterotoxins by blocking the Cl- channel on the intestinal epithelium. Wood creosote also decreases intestinal motility accelerated by mechanical, chemical, or electrical stimulus by the inhibition of the Ca2+ influx into the smooth muscle cells. In this overview, the antimotility and antisecretory effects of wood creosote are compared with those of loperamide. Wood creosote was observed to inhibit stimulated colonic motility, but not normal jejunal motility. Loperamide inhibits normal jejunal motility, but not stimulated colonic motility. Both wood creosote and loperamide inhibit intestinal secretion accelerated by acetylcholine. Wood creosote was found to have greater antisecretory effects in the colon than loperamide. Based upon these findings, we conclude that the antidiarrheal effects of wood creosote are due to both antisecretory activity in the intestine and antimotility in the colon, but not due to the microbicidal activity as previously thought. Wood creosote was found to have no effects on normal intestinal activity. These conclusions are supported by the results of a recent clinical study comparing wood creosote and loperamide, which concluded that wood creosote was more efficacious in relieving abdominal pain and comparable to loperamide in relieving diarrhea.
In pharmaceutical industries, most active pharmaceutical ingredients are poorly water soluble, and therefore milling processes are important to obtain fine particles that can be easily dissolved in the body. However, the main purpose of milling is micronization of particles. From the viewpoint of fine particle preparation in the formulation process, milling has not been investigated sufficiently. In this paper, ethenzamide was milled under various operating conditions using a fluidized-bed jet-mill. It was found that not only the particle size but also the particle shape varied with the milling conditions. The relationship between particle shape and milling conditions has been obtained experimentally.
The proclamation of April 2002 of a Ministry of Health, Labor and Welfare ordinance has enabled doctors to prescribe drugs for an outpatient without a limit on the length of prescription terms except for a few drugs. There is a concern that the prescription-term deregulation could cause careless drug therapy management in order to extend the interval between patient hospital visits. The purpose of this study is to make pre- and post-deregulation comparisons of two items, prescription terms and implementation of clinical examination that complied with package-insert precautions, and to discuss the approaches to increase safety. Prescription terms have lengthened progressively. In the pre-regulation period of January to March 2002, the mean prescription term was 19.9 days; in the post-regulation period of July to September 2002, it was 24.9 days; and in July to September 2003, 28.6 days. Even for anti-tumor agents, there were prescriptions over 90 days after deregulation. There was no significant difference between the pre- and post-deregulation compliance ratios for the package-insert precautions in eight drugs of investigated nine. However, one case had a delay in detection of liver dysfunction, which was caused by deviation from the once-a-month testing indicated in the package-insert precautions for prolonged prescription terms. The evidence suggested that the deregulation led to negligent drug therapy management. To assure safe therapy, the following should be addressed: first, sufficient function of a computerized prescriber order entry system and second, creation of a new framework with pharmacists' active involvement such as collaborative therapy management with physicians.
This paper describes the mapping of the inner cavity of cyclodextrin and the guest molecule using the cylindrical coordinate system. Each cavity structure of α-, β-, and γ-cyclodextrin was examined using the coordinate system, in which, the Z-axis passes through the molecular axis; a normal of the plane that consists of 6, 7, or 8 C1 atoms of glucose units was obtained using the least-squares methods and that passes through the center of C1 atoms. The radius ρ is the distance from the Z-axis to the solvent-accessible surface of a cavity. The φ-axis is defined such that the nearest C1 atom of the glucose unit to the Z-axis is its origin. The atomic character of the inner surface of the cavity was also obtained and plotted in the same coordinates. The guest molecule was plotted with the same coordinate system as cyclodextrin to see atoms with large ρ distance of the guest molecule on the solvent-accessible surface map of cyclodextrin. It was confirmed from the map that cyclodextrin molecules have an ellipsoidal shape, have pseudo-n-hold symmetry (n=6 to α, 7 to β, and 8 to γ) in relation to their molecular axis, and guest molecules are located in relatively hydrophobic regions. It was also confirmed that the maps of this system give insights into the complementary characters of structures between the host and the guest by plotting the guest molecule in the same coordinate system.
Lycium barbarum is one of the traditional oriental medicines. It has been reported to reduce blood glucose levels. In this study, the effect of Lycium barbarum polysaccharide (LBP) on the improvement of insulin resistance and lipid profile was studied in rats, a model for non-insulin dependent diabetes mellitus (NIDDM). The rats were divided into three groups: control, NIDDM control, and NIDDM+LBP. Diabetes model groups were made by feeding high-fat diet and subjecting to i.p. streptozotocin (50 mg/kg). LBP treatment for 3 weeks resulted in a significant decrease in the concentration of plasma triglyceride and weight in NIDDM rats. Furthermore, LBP markedly decreased the plasma cholesterol levels and fasting plasma insulin levels, and the postprandial glucose level at 30 min during oral glucose tolerance test and significantly increased the Insulin Sensitive Index in NIDDM rats. In the present study, we have tested that LBP can alleviate insulin resistance and the effect of LBP is associated with increasing cell-surface level of glucose transporter 4 (GLUT4) in skeletal muscle of NIDDM rats. Under insulin stimulus, GLUT4 content in plasma membrane in NIDDM control rats was significantly lower than that of control (p<0.01), and GLUT4 content in the plasma membrane in NIDDM+LBP rats was higher than that of NIDDM control rats (p<0.01). In conclusion, LBP can ameliorate insulin resistance, and the mechanism may be involved in increasing cell-surface level of GLUT4, improving GLUT4 trafficking and intracellular insulin signaling.
Since it is necessary to make more physicians and nurses fully understand the in-hospital pharmacist's work, a questionnaire survey was performed for physicians and nurses on their knowledge of and satisfaction with the work. The survey results were analyzed with multiple regression analysis to reflect the results specifically and objectively in the routine activities of the pharmacy. The results showed that physicians with experience of less than 1 year were not well aware of the pharmacists' work related to clinical trials and therapeutic drug monitoring, and that those with an experience of 1 year or longer were not well aware of the work related to clinical trials. Nurses with an experience of less than 5 years or 5 years or longer were not well aware of the work related to in-hospital pharmaceutical preparations. The pharmacists' work that affected the satisfaction of physicians and nurses include the provision of drug information, checking of prescriptions, guidance of patients on drug compliance, and management of nonprescription and poisonous drugs. The present multiple regression analysis was useful for understanding the current status of in-hospital jobs and objectively distinguishing jobs to be improved from those that might be continued in the present manner. Multiple regression analysis may be a useful analytical tool for improving pharmacists' work.
The safety of pharmaceuticals has become increasingly important not only in daily medical treatment but also in clinical trials. Although clinical laboratory data are more objective than clinical symptoms, the determination as to whether they indicate abnormal variations depends largely upon the clinical judgment of physicians. The process of determination has not been sufficiently objectified. The present study investigated the indices of criteria for variations in clinical laboratory data obtained in clinical trials. Then, detection rates of abnormal variations were compared between our determination method that employs the reference change value (RCV) expressing the width of biological variation for each test component and conventional determination methods. The study also demonstrated that by combining standard values and the RCV for determination, abnormal variations were found at a rate greater than 50%. The method we propose was applied to the safety evaluation of pharmaceuticals. In clinical trials on the antiviral drug ribavirin administered alone, components of laboratory tests were selected that should be noted in studies on its effects. Expect for decreases in red blood cell counts and hemoglobin values, which are closely associated with anemic symptoms and well known to hepatologists, the increasing trend in platelet counts and decreasing trend in albumin were found to be laboratory test components that should be paid attention to, even though they may not be obvious.
Apigenin 7-O-β-D-glucopyranuronide (1), luteolin 7-O-β-D-glucopyranuronide (2), m-hydroxybenzyl β-D-glucoside (3), and chrysoeriol 7-O-β-D-glucopyranuronide (4) were isolated for the first time from the leaves of Salix matsudana. Furthermore, the effects of compounds 1, 2 and 3 on arachidonic acid metabolism were studied. These compounds inhibited significantly the production of 12-hydroxy-5, 8, 10, 14-eicosatetraenoic acid (12-HETE). In addition, the aglycon apigenin inhibited not only 12-HETE but also thromboxane B2 (TXB2). The effect of compound (4) on arachidonic acid metabolism is now under investigation.
This study aimed to examine the effects of banana juice on levodopa bioavailability in rats. When a levodopa preparation (EC-Doparl tablets) was orally administered with banana juice made by mixing with a fresh banana and water, there were significant decreases in Cmax (17.4±2.5 vs. 8.6±3.1 μg/ml; α=0.05) and AUC (1882.8±49.2 vs. 933.5±286.6 μg•min/ml; α=0.05) for levodopa. On the other hand, administration of the levodopa preparation with a commercial beverage containing 10% banana juice resulted in no significant change in Cmax or AUC. These results indicate that concomitant intake of levodopa preparations with banana juice, but not with a commercial banana beverage, may cause a drug-food interaction reducing levodopa bioavailability, and we should pay attention to such interactions during levodopa therapy for patients with Parkinson's disease.