My main research fields are powder technology, especially solid dosage form, from basic ones to applied ones. Basic ones are physical properties of powder and its packing, compression and computer simulation. Applied ones are preparation and evaluation of granulation, tableting, improvement of solubility of water poor-soluble drug, controlled release tablet and fast disintegrating tablet in the oral cavity. As the chair man of the Standard Formulation Research Council, I have obtained many variable and excellent results. Several results are shown as follow.
The broad substrate tolerance and catalytic potential of squalene cyclizing enzymes of bacterial and plant origin are remarkable; the enzymes readily accept variety of non-physiological substrate analogues and efficiently perform sequential ring-forming reactions to produce a series of unnatural cyclic triterpenes. By utilizing the catalytic plasticity of the enzymes, it is possible to generate unnatural novel cyclic polyprenoids by enzymatic conversion of chemically synthesized substrate analogues. Here we present recent examples including (a) enzymatic formation of a “supra-natural” hexacyclic polyprenoid as well as heteroaromatic ring containing cyclic polyprenoids by bacterial squalene: hopene cyclase from Alicyclobacillus acidocaldarius, and (b) enzymatic cyclization of 22,23-dihydro-2,3-oxidosqualene and 24,30-bisnor-2,3-oxidosqualene by plant oxidosqualene: β-amyrin cyclase from Pisum sativum.
Recent biological and pharmacological studies strongly suggested that plant polyphenols in foods, beverages and crude drugs have various health benefits. However, still there are chemically uncharacterized polyphenols, especially those with large molecular weights. The typical example is black tea polyphenols. Four tea catechins of fresh tea leaves are enzymatically oxidized in tea fermentation process of black tea manufacture to give a complex mixture of the oxidation products. Despite many efforts since 1950's, major part of the black tea polyphenols has not been clarified yet. We have investigated the oxidation mechanism of each catechin by employing a newly developed in vitro model fermentation system. The oxidation was initiated by enzymatic dehydrogenation of catechins, and subsequent intermolecular quinone-phenol coupling reactions followed by cascade-type degradation of the unstable products resulted in the formation of complex black tea polyphenols. Besides black tea polyphenols, this review introduces the chemistry of insolubilization of persimmon proanthocyanidins, wood polyphenols in connection with whisky polyphenols, and co-polymerization of cinnamaldehyde and proanthocyanidins in cinnamon bark.
New possibilities for catalytic syntheses of lactone derivatives and nitrogen-containing heterocyclic compounds in fluorinated alcohols are described. The cationic Rh(I) catalyst in fluorinated alcohol solvents (hexafluoroisopropanol: HFIP, trifluoroethanol: TFE) brought about not only mild cycloaddition reactions of ester-tethered compounds but also a facile formation of indole derivatives by the aromatic amino-Claisen rearrangement of N-propargyl aniline derivatives. The use of HFIP as an additive exerted a remarkable effect on the Pictet-Spengler reaction catalyzed by the fluorinated surfactant-combined Brønsted acid catalyst in water.
We have developed a novel and practical synthetic method for functionalized benzofurans via the route involving [3,3]-sigmatropic rearrangement of N-trifluoroacetyl enehydroxylamines, which was triggered by acylation of oxime ethers. Treatment of oxime ethers with trifluoroacetic anhydride (TFAA) gave dihydrobenzofurans while reaction of the identical oxime ethers with trifluoroacetyl triflate (TFAT) in the presence of DMAP afforded aromatized benzofurans without the isolation of enehydroxylamines. It is noteworthy that either dihydrobenzofurans or benzofurans can be formed selectively from the same substrate by changing only the reagent. TFAA has been proved to be the good reagent to induce regioselective [3,3]-sigmatropic rearrangement for the synthesis of hexahydrodibenzofurans with a quaternary carbon. On the other hand, the TFAT-DMAP system is found to be the most effective for constructing 2-arylbenzofurans. Synthetic utility of these selective constructions is demonstrated by the formal total synthesis of (±)-lunarine and the short synthesis of natural 2-arylbenzofurans.
We studied the antioxidant and antibacterial activities of monomeric and dimeric phenol compounds. Dimeric compounds had higher antioxidant activities than monomeric compounds. Electron spin resonance spin-trapping experiments showed that phenol compounds with an allyl substituent on their aromatic rings directly scavenged superoxide, and that only eugenol trapped hydroxyl radicals. We developed a generation system of the hydroxyl radical without using any metals by adding L-DOPA and DMPO to PBS or MiliQ water in vitro. We found that eugenol trapped hydroxyl radicals directly and is metabolized to a dimer. On the other hand, dipropofol, a dimer of propofol, has strong antibacterial activity against Gram-positive bacteria. However, it lacks solubility in water and this property is assumed to limit its efficacy. We tried to improve the solubility and found a new solubilization method of dipropofol in water with the addition of a monosaccharide or ascorbic acid.
Ashwagandha (root of Withania somnifera) has been used for many purposes, it is mainly considered a tonic in traditional Ayurvedic medicine. This review focuses on the effects of compounds isolated from Ashwagandha on dementia models and on the spinal cord injury model. Our study demonstrated that the active constituents, withanolide A, withanoside IV, and withanoside VI, restored presynapses and postsynapses, in addition to both axons and dendrites in cortical neurons after Aβ(25-35)-induced injury. In vivo, oral withanolide A, withanoside IV, and withanoside VI (10 μmol/kg/day for 12 days) improved Aβ(25-35)-induced memory impairment, neurite atrophy, and synaptic loss in the cerebral cortex and hippocampus in mice. Since spinal cord injury (SCI) is also difficult to treat, and therefore practical and curable strategies for SCI are desired. Oral treatment with withanoside IV improved locomotor functions in mice with SCI. In mice treated with withanoside IV (10 μmol/kg/day for 21 days), the axonal density and peripheral nervous system myelin level increased. The loss of CNS myelin and increase in reactive gliosis were not affected by withanoside IV. Additionally, sominone, an aglycone of withanoside IV, was identified as the main metabolite after oral administration of withanoside IV in mice. Withanolide A, withanoside IV, and withanoside VI are therefore important candidates for the therapeutic treatment of neurodegenerative diseases. In particular, withanoside IV was shown to control neurons as well as glial cells for reconstruction neuronal networks. To clarify key events in overcoming neurodegeneration, we are now studying the molecular targets and signal cascades of sominone.
O-Silyl cyanohydrins of β-silyl-α,β-epoxyaldehyde can function as a highly functionalized homoenolate equivalent via a tandem sequence involving base-promoted ring opening, Brook rearrangement, and alkylation at the allylic position. We named this rearrangement epoxysilane rearrangement. Based on results of mechanistic studies involving competitive experiments using diastereomeric cyanohydrins, we propose a reaction pathway involving a silicate intermediate formed by a concerted process via an anti-opening of the epoxide followed by the formation of an O-Si bond. Moreover, results of mechanistic studies on the rearrangement led to a conceptually novel approach to the chirality transfer in which epoxide chirality can be transferred into carbanion. We demonstrate the usefulness of the rearrangement through application to the following reactions: (1) reaction of γ-p-toluenesulfonyl-α,β-epoxysilane with alkyl halides and aldehydes followed by treatment with n-Bu4NF, which affords α,β-unsaturated aldehydes (2) reaction of γ-phosphonio-α,β-epoxysilane with aldehydes, which affords dienol silyl ether derivatives (3) reaction of an enoate bearing an eposysilane moiety at the α-position with lithium enolate of 2-chloroacetamide, which affords highly functionalized cyclopropane derivatives.
N-Heterocyclic carbenes have been studied for their ability to catalyze C-C bond formations and asymmetric reactions. The fluoro groups of fluorobenzenes are nucleophilically substituted with aroyl groups derived from aromatic aldehydes due to the catalytic action of imidazolidenyl carbenes to afford ketones. N-Heterocyclic carbenes mediate the addition of trimethylsilyl cyanide to aldehydes to yield cyanohydrin trimethylsilyl ethers. The use of chiral imidazolidenyl carbenes derived from (R,R)-1,3-bis[(1-naphthyl)ethyl]imidazolium chloride led to enantioselective cyanosilylation. C2-symmetric imidazolidenyl carbenes catalyze the asymmetric acylation of racemic secondary alcohols.
Glycosphingolipids (GSLs) are contained in a various cell membranes and have recently been implicated in many physiologic functions. They are classified based on their sugar moieties into ceramides, cerebrosides, sulfatides, ceramide-oligohexosides, globosides, and gangliosides. A number of GSLs have been obtained from marine invertebrates such as echinoderms, poriferans, and mollusks and have unique biological activities. During the course of our search for biologically active GSLs from echinoderms, we conducted the isolation and structural elucidation of GSLs from starfish and feather stars and found numerous GSLs, some of which have unique structures. In particular, gangliosides from feather stars were unique in that the sialic acids bind to inositol-phosphoceramide. We also found that the GSLs from starfish and feather stars possess neuritogenic activity toward the rat pheochromocytoma cell line PC12, antihyperglycemic effects against type 2 diabetic BKS. Cg-m+/+Leprdb/J (db/db) mice, and antiosteoporosis effects toward the osteoporosis model mice (OVX mice). These biological activities are thought to be related to dementia, osteoporosis, and diabetes, which are becoming social problems, and are expected to become the seeds of preventive or therapeutic drugs for these illness.
We reported that ginger prevented obesity in mice fed a high-fat diet in previous study. In this experiment, we examined the effects of zingerone, the major pungent component of ginger on fat storage in ovariectomized (Ovx) rats. Oral administration of 170 mg/kg zingerone significantly reduced body weight and the final parametrail adipose tissue weight in ovariectomized rats. Blood glucose levels after oral administration of glucose were lower in zingerone-treated Ovx-rats than in the Ovx-rats (control). Basal lipolysis in zingerone-treated Ovx-rats was increased compared with that in the Ovx-rats. Zingerone significantly increased norepinephrine-induced lipolysis associated with the translocation of hormone-sensitive lipase (HSL) from the cytosol to lipid droplets in adipocytes. These results indicate that zingerone may prevent the fat storage through increasing norepinephrine-induced lipolysis in adipocytes.
Glutathione dose dependently inhibited melanin synthesis in the reaction of tyrosinase and L-DOPA. The inhibition of melanin synthesis was recovered by increasing the concentration of L-DOPA, but not recovered by increasing tyrosinase. Glutathione inhibited the binding between tyrosinase and L-DOPA. Although the synthesized melanin was aggregated within 1 h, the aggregation was inhibited by the addition of glutathione. These results indicate that glutathione inhibits the synthesis and agglutination of melanin by interrupting the function of L-DOPA.
Background: The carboplatin (CBDCA) dosage is usually calculated using the formula of Calvert. Instead of the glomerular filtration rate (GFR), 24-h creatinine clearance (24 CLcr) is often used in this formula, which is calculated based on 24-h urine collection in clinical practice. Objective: We studied the adequacy of 24 CLcr in calculating the appropriate dosage of CBDCA using the formula of Calvert and compared CLcr and GFR using various substitutable predictive formulas (the formulae of Cockcroft and Gault, Yasuda, Orita, Jellife, Mawer, MDRD, and modified MDRD) when we were not able to use 24 CLcr. Methodology: We retrospectively studied 193 patients who received CBDCA as chemotherapy during the period April 2004 through November 2006. We evaluated the adequacy of 24-h urine collection for measurement of creatinine production and excretion. We also evaluated the appropriate urine collection within a 15% range of the difference. The correlation between the appropriate 24 CLcr resulting in the urine collection and the CLcr or GFR was examined using past predictive formulae in the patients with appropriate urine collection. Results: The accuracy of 24 CLcr was evaluated in 83 patients (43%). There was a significant correlation between CLcr or GFR using various predictive formulas and the appropriate 24 CLcr. There was an especially close and significant correlation with the formulae of Cockcroft and Gault and Yasuda (r>0.950, p<0.001). Conclusion: When using the Calvert formula, the accuracy of 24 CLcr should be evaluated. Patients evaluated as having inaccurate urinary collection should use the formulae of Cockcroft and Gault and Yasuda.
Clinical pharmacy practice needs quality safeguards and proper evaluation to ensure good performance of hospital pharmacists. We propose a method for evaluating performance using the indicator of whether pharmaceutical interventions conducted in clinical practice affect the treatment carried out by the physician. To illustrate the usefulness of this method, we report one example of the response of a physician to our clinical practice. We first designed a worksheet on which information related to pharmaceutical interventions would be recorded. The worksheet included sections for the details of the pharmaceutical intervention, whether decisions about interventions were active (pharmacists' decisions) or passive (requests from the physician), the timing of the intervention (before or after prescription), the grounds for the intervention, and whether it had any influence on the treatment, as well as a detailed record of the course of the intervention. These worksheets were used to record pharmaceutical interventions from July to December 2005. During that period, a total of 347 pharmaceutical interventions for 164 patients were recorded. Each intervention was examined from the different perspectives of type of intervention, timing (before or after prescription was issued), and reason for the intervention. Overall, it was found that 91.6% of all interventions had some influence on treatment. Because numerical results can be obtained with this method, it has the benefit of being an objective means of evaluating the contribution of pharmaceutical services. Furthermore, the validity of even those interventions that had no influence on treatment can be examined using medical and pharmaceutical findings and may improve the quality of pharmacists.
Impetigo contagiosa staphylogenes is commonly treated by administering a combination of nadifloxacin and tetracycline ointments. However, it is not clear whether nadifloxacin and tetracycline are stable after mixing. The purpose of this study was to evaluate the stability of these agents in combination. We also evaluated changes in antibacterial activity after mixing. Mixing the two ointments caused tetracycline to change from yellow to brown in the admixture. Furthermore, the tetracycline content in the ointment decreased in a time-dependent manner, to about 40% at 288 h after mixing. In addition, the nadifloxacin content in the ointment did not change 288 h after mixing. In an alkaline environment (pH 9.0 and 11.0), the tetracycline content decreased and the color of tetracycline changed to brown. These results suggest that sodium hydroxide, which is an additive in nadifloxacin ointment, influences the content of tetracycline. We evaluated the chemical sensitivity of Staphylococcus aureus using disk tests. Nadifloxacin and tetracycline ointment showed the largest radius of inhibition circle, followed by the admixture 0 h after mixing and the admixture 72 h after mixing. These results suggest that the antibacterial activity is inhibited by the admixture. We propose that pharmacists should avoid mixing nadifloxacin with tetracycline ointment in the treatment of impetigo contagiosa staphylogenes and should take care to avoid interactions caused by additives in the ointments.
To evaluate the cardio pulmonary resuscitation(CPR)/automated external defibrillator(AED)operation class and disability (wheelchair, inconvenience, and eye mask) experiences class provided as part of the 2007 early exposure program at Gifu Pharmaceutical University, a questionnaire survey was conducted among students who had participated in this program. Many students had already participated in a previous CPR class (79%) and/or disability experiences class (55%), and some students had even experienced a real-life situation requiring these techniques (9% and 14%, respectively). Those with previous training experience performed more effectively in this year's early exposure program than those without such an experience. Due to the active participation of most students during the training, a significantly higher level of satisfaction with the program than that previously expected was achieved (mean score on a 5-grade scale: 3.98 vs. 3.31 for the CPR/AED class; 4.35 vs. 3.69 for the disability experiences class). Furthermore, many students commented that their experience in this year's program increased their motivation for future training and confidence to cope with a real-life situation in the future. These findings demonstrated the effectiveness of repeated training in mastering the CPR/AED and welfare-related techniques, and the usefulness of incorporating such training into the early exposure program. To provide regularly a meaningful early exposure program, the concept of a “model core curriculum” led by learners as well as the age-mixing method with senior students supporting instruction of their juniors should be introduced.