Research works on molecular interactions in solutions were carried out at School of Pharmacy, the University of Wisconsin under the direction of Prof. T. Higuchi and at Faculty of Pharmaceutical Sciences, Kyoto University under the direction of Prof. H. Sezaki. Studies on permeation of drugs through polymer membranes were carried out at Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada and at Pharmaceutical Chemistry Research Laboratories at Food and Drug Directorate, Department of Health and Welfare, Canada. Studies on modification of delivery patterns by means of pharmaceutical approaches were carried out at Faculty of Pharmaceutical Sciences, Hokkaido University. Topics related to modification of drug delivery patterns include employment of amorphous forms such as ground mixture with micro-crystalline cellulose and coprecipitate with polyvinylpyrrolidone, use of biodegradable polymers such as polylactic acid and polycarbonates, gel-forming materials such as konjac, agar and hydroxypropylcellulose, and physicochemical systems such as complexation. Works related to drug delivery and disposition of drugs in humans were carried out at Department of Pharmacy, Kumamoto University Hospital. Topics related to drug delivery in humans include injections containing anticancer drugs for intra-arterial administration, lidocaine gels for dermal anesthesia, glucagon solution for nasal administration. Topics related to disposition of drugs in humans include clinical pharmacokinetic studies in infants and elderly and medical uses of adsorbents.
Gyokuheifusan (GHS, Jade Windscreen Powder in English, Yupingfengsan in Chinese) is an herbal formula in traditional Kampo medicine which consolidates superficial resistance to protect against invasion by external pathogens. This review describes the immunopharmacologic properties of GHS as a holistic Kampo medicine, which can affect human homeostasis and constitution of human beings. Oral treatment with GHS has preventive and curative effects in allergic rhinitis induced by Japanese cedar pollen in guinea pigs. Since these effects do not occur with authentic antiallergic agents, GHS appears to have holistic effects on allergic rhinitis. In another study, the effects of GHS on murine antibody production against ovalbumin (OVA) were evaluated. When mice were sensitized intraperitoneally to OVA, the concentration of OVA-specific immunoglobulins in the sera significantly increased with GHS treatment. When they were sensitized intranasally to OVA, GHS significantly reduced the concentration of OVA-specific antibodies in the sera. It was suggested that GHS stimulats immune responses when the antigen had already invaded the body, and that GHS might consolidate the resistance of nasal mucosa to protect from OVA invasion, and then OVA-specific antibodies in sera might be suppressed. These results suggest that traditional medicines have own characteristics different from those of modern medicines, and that original pharmacologic experiments are important to evaluate traditional medicines scientifically.
A dual-color enzyme-linked immunospot (ELISPOT) assay enabled us to analyze three types of cytokine-secreting cells simultaneously. T helper (Th) cells can be subdivided into at least two distinct functional subsets based on their cytokine secretion profiles. The first type of clones (Th1) produces interleukin-2 (IL-2) and interferon-γ (IFN-γ), but not IL-4 or IL-5. The second type of clones (Th2) produces IL-4 and IL-5, but not IL-2 or IFN-γ. Furthermore, the presence of the third type (Th0) of cell, which is a precursor of Th1 or Th2 cells, has been demonstrated to produce both Th1- and Th2-type cytokines. The dual-color ELISPOT assay was developed to differentiate these three subtypes of Th cells in an identical well. In the system, the red spots corresponding to IL-2-secreting cells (Th1) were developed with horseradish peroxidase and aminoethylcarbazole/H2O2. The light-blue spots corresponding to IL-4-secreting cells (Th2) were developed with alkaline phosphatase and Vector blue (chromogenic substrate for alkaline phosphatase). The mixed-colored (indigo) spots corresponding to both types of cytokine-secreting cells (Th0-cells) were developed with both chromogenic substrates. With this system, we could detect the IL-2- and/or IL-4-secreting cells simultaneously in a murine spleen cell or human peripheral mononuclear cell preparation.
Sho-saiko-to (Xiao-Chai-Hu-Tang), one of the major traditional Chinese medicines, has been frequently prescribed with other synthetic or biotechnological drugs for the treatment of various acute or chronic diseases in Japan, and thus it is important to understand the interactions between Sho-saiko-to and coadministered drugs. This paper reviews the effects of Sho-saiko-to on the pharmacokinetics and pharmacodynamics of concomitant drugs in the gastrointestinal tract. Sho-saiko-to slightly hastens the gastrointestinal absorption of the sulfonylurea compound tolbutamide. Furthermore, it is considered that the increase in the gastrointestinal absorption rate by Sho-saiko-to may potentiate the hypoglycemic effects of tolbutamide in the early period after oral administration. Sho-saiko-to can facilitate the epithelial membrane permeability of tolbutamide at an early phase across the rat jejunum in situ and Caco-2 cell monolayers. It is also suggested that Sho-saiko-to enhances the energy-dependent transport of tolbutamide and has an inhibitory effect on the passive paracellular transport of tolbutamide in Caco-2 cells. This result might be related to the accelerated in vivo absorption rate of tolbutamide by concomitant dosing with Sho-saiko-to in rats. In addition, Sho-saiko-to has inhibitory effects on the efflux pump mediated by MDR1, and it appears that the crude constituents in Glycyrrhizae radix, glycyrrhizic acid and liquiritin, contribute to MDR1 suppression.
Eugenol, isoeugenol, caffeic acid, ferulic acid, isoferulic acid, estragole, trans-anethole, and paeonol are components of a Chinese herbal medicine used as a painkiller and stomachic. We investigated the potential role of these compounds as antioxidants. We studied the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical-scavenging effect of these molecules, together with some glycoside derivatives, to ascertain their potential in reducing the levels of activated oxygen species in vivo. The DPPH radical-scavenging effects of eugenol, isoeugenol, and the glycoside derivatives of caffeic acid, ferulic acid, and isoferulic acid (SC50=8—28 μM) were similar to those of α-tocopherol, which was used as a positive control.
Various drug-induced taste disorders have been ascribed to zinc deficiency in serum. Assuming that the zinc deficiency is caused by the chelating reaction of zinc ions with drugs, the electrode potential of the Zn2+/Zn(Hg) system was measured in the presence of drugs in water, ethanol, and N,N-dimethylformamide (DMF). The zinc-chelating ability was estimated based on the potential change ΔE2 with the addition of a drug. A large potential change suggesting potent chelating ability was observed in penicillamine, furosemide, and ibuprofen in ethanol and in fluorouracil, acetazolamide, and bezafibrate in DMF. Multiple regression analysis was used to evaluate the observed ΔE2 in mV to represent chelating ability. The regression equation to estimate the frequency of taste disorders was deduced from ΔE2, and frequency of four drugs appeared in package inserts and interview forms. According to the regression equation, the frequency of taste disorders was successfully estimated for 14 drugs examined in this study. The result was examined in a clinical case.
We examined mechanoradical formation in the grinding process of commercial tablets using electron spin resonance (ESR). Mechanoradicals were detected in all tested samples (23 types of commercial tablets) when the ball-milling of tablets was conducted under anaerobic conditions and some were fairly stable even in air. Thus the grinding may cause changes in the physicochemical properties of ingredients included in commercial tablets. Because high quality is demanded in pharmaceuticals, these results suggest more caution should be taken in the grinding of commercial tablets in hospitals and pharmacies.