The constituents of Citrus plants were investigated to develop useful agents that are effective in cancer chemoprevention. We examined the roots and bark of the roots of various Citrus plants, resulting in the isolation of many novel compounds. Their structures were determined using spectroscopic methods, especially 2D-NMR spectra. The following new compounds of constituents were found: dimeric coumarins, dimeric acridone alkaloids, and acridone-coumarin dimers. Auraptene and nobiletin are known as useful constituents of the peel of Citrus plants for cancer chemoprevention. However, we found that 3,5,6,7,8,3′,4′-heptamethoxyflavone (HPT) has both antitumor promotion and initiation activities and is more effective than auraptene and nobiletin. We synthesized pentaallyl quercetin (QPA), a useful antitumor compound that has the additional effects of a P-glycoprotein (P-gp) inhibitor. The inhibitory effects of QPA on P-gp were more effective than those of the typical P-gp inhibitors cyclosporin A and verapamil. Both HPT and QPA have antitumor promotion activity and are potential candidates for effective multidrug resistance agents in cancer chemotherapy.
The present study examined the phototoxicities of a series of 7-(3-aminopyrrolidinyl) quinolones containing various substituents at position 1 by use of a mouse model. For the 7-(3-aminopyrrolidinyl) quinolones with a halogen atom at position 8, well-known substituent groups such as a cyclopropyl, an ethyl, or a difluorophenyl at position 1 were found to be responsible for severe phototoxicity. However, when an aminodifluorophenyl or an isoxazolyl group was placed at position 1, even 8-halogeno quinolones were found to be mildly phototoxic. This is the first report of 8-halogeno quinolones that are not severely phototoxic. Two structurally similar 8-chloro quinolones (the 1-aminodifluorophenyl 8-chloro quinolone and the 1-difluorophenyl 8-chloro quinolone) were investigated further. The former was mildly phototoxic; the latter was severely phototoxic. We demonstrate that these two 8-chloro quinolones have practically the same areas under the concentration-time curves from 0 to 4 h in auricular tissue, suggesting that the mild phototoxicity is not due to pharmacokinetic instability. The rates of UV photodegradation of these compounds were also measured. We found that these two quinolones photodegrade at similar rates, suggesting that the mild phototoxicity is not attained through increased photostability. In conclusion, the phototoxic potentials of fluoroquinolones are influenced not only by the substituent at position 8 but also by that at position 1. We also discovered a mildly phototoxic 8-chloro quinolone which did not have increased photostability.
Calixarene libraries consisting of ca. 50000 members substituted with peptides at the lower rim were synthesized using encoded spilt synthesis with 15 amino acids. Screening of the library for binding with a dye-labeled oligopeptide indicated that some peptidocalixarenes selectively bind the oligopeptide. The binding constant was estimated to be approximately 2×104 mol dm-3. In an attempt to develop chemical sensors for peptides, fluorescence-labeled peptidocalixarene libraries consisting of ca. 3500 members were synthesized. The fluorescence spectrum of peptidocalixarene, which was found in the screening of libraries against the target peptide, was dependent on the concentration of the peptide. The libraries substituted at the upper rim were also synthesized with the aim of developing more selective and sensitive chemical sensors. The binding selectivity of the library members for the target peptides was higher and the behavior of the sensing was markedly different from the lower rim-modified peptidocalixarene sensor.
The implementation of Iyaku Bungyo, the changed regulations for drug distribution and the proposed change of pharmacy education from a four-year program to a six-year program are rapidly changing the practice of pharmacy. However, pharmacists' activities still remain at the level of simple dispensing and selling of drugs. Also, the terms that describe the essence of pharmacists' activities, such as services in patient care areas are still unclear. In order to solve and improve the problem of terminology for pharmacists' activities the use of terms related to pharmacists' services were examined in historical context. It was found that the terms “Rinsho yakugaku” and “Iryo yakugaku” have been used as having a similar meaning. Further, the term “Iryo yakugaku” was used to denote the comprehensive scope of pharmacists' services including “Rinsho yakugaku”. It was verified that “Rinsho yakugaku” is a valid translation for “clinical pharmacy”. “Iryo yakugaku” has a more comprehensive translation than “pharmaceutical care”, therefore, it appears that “Iryo yakugaku” is a suitable translation for “pharmaceutical services”. Hence, we proposed “Iryo yakugaku” as the English translation for “pharmaceutical services” and “Chiryo yakugaku” as the Japanese translation for “pharmaceutical care”. There is a need, however for further clarification and definition of pharmacists' activities.
In Japan, pharmacists' activities for the most part consist of dispensing although in some University Hospitals they are directly involved in patient care. In the United States, pharmacists' activities have evolved over forty years in providing drug therapy and have now expanded to improvement in the patient's quality of life. In addition, a six-year pharmacy education program based on patient care is now in place nationally. Furthermore, World Health Organization (WHO) and International Pharmaceutical Federation (FIP) have made recommendations on pharmacists' activities. Shifting to a six-year pharmacy education in Japan has now been decided, and new approaches are being proposed. For pharmacists to serve society in their role as health care professionals, one needs to examine the activities they are expected to perform and pharmacy education necessary to develop these skills. In this paper, pharmacy education was examined by analyzing and comparing Western countries and Japan, with a focus on Canadian pharmacists' activities and pharmacy education in Alberta.
Although disease-modifying antirheumatic drugs (DMARDs) are used in the treatment of rheumatoid arthritis (RA), the selection of agents in the case of relapse (escape phenomenon) lacks clear-cut standards. Therefore we investigated the rate and conditions of escape as well as the agents used after escapes had occurred. Outpatients of the Matsubara Mayflower Hospital with a history of DMARD administration during the 4 years prior to May 2003 were studied. Those receiving salazosulfapyridine (SASP) had a high escape rate and those receiving methotrexate (MTX) and bucillamine (BC) had a low rate. The continuous duration of administration was long for MTX and BC, but short for sodium aurothiomalate (GST). BC and Actarit (AR) gradually elevated C-reactive protein (CRP) levels and the erythrocyte sedimentation rate (ESR). In patients receiving SASP and MTX, a high level of CRP and high ESR was seen 2 months prior to the occurrence of escape and remained unchanged after escape. With respect to the agents used after escape, SASP and BC were substituted with other DMARDs. A combination with other DMARDs was usually administered to patients who had been receiving MTX. Taken together, the present results clarified the characteristics of DMARD escape and will contribute to the appropriate pharmacotherapy for RA.
In general, spectrophotometric methods (inductively coupled plasma or atomic absorption spectrophotometry) are used for the assay of magnesium stearate (Mg-St). In this study, a new rapid, selective assay method was developed for Mg-St in pharmaceutical formulations. The method was based on isocratic reverse-phase liquid chromatography using a mobile phase of acetonitrile-water (80:20, v/v) after precolumn derivatization with 2-nitrophenyl hydrazine for sensitive UV detection. Margaric acid was used as an internal standard and the substances were detectable at 230 nm or 400 nm. Using a short (2 cm) HPLC column reduced the analytical time to 5 min. Validation of the newly developed method was performed in accordance with the International Conference on Harmonization guidelines. The linearity range for Mg-St was 0.00—0.04 mg/ml (as the concentration of injected sample solution) and their correlation factor was 0.9998. The determination and detection limits for Mg-St were 6 μg and 2 μg, respectively. The proposed method was successfully applied to the determination of trace amounts of Mg-St in commercially available tablets with a high recovery percentage, good accuracy, and precision.
Diazepam is commonly used as premedicant for endoscopic procedures. Wide interindividual differences have been observed in the residual cognitive effects of the drug after gastrointestinal endoscopy. Our aim was to clarify the major factors, including pharmacokinetic factors, contributing to this wide variation in residual cognitive effect after gastrointestinal endoscopy in the study. Sixty-one outpatients undergoing gastrointestinal endoscopy participated in the study. Cognitive effects were evaluated in the diazepam group (n=52) by the digit symbol substitution test (DSST) twice before and 30 min after an intravenous administration of 5 mg diazepam; in the intervening time gastrointestinal endoscopy was performed. Plasma concentrations of diazepam were determined by HPLC. The control group (n=9) was tested by DSST in the same manner. The cognitive effects according to the change in DSST score was significantly decline in the diazepam group compared with the control group (by 0.2 versus -4.6; P=0.014). This prospective study confirmed that cognition was significantly impaired after gastrointestinal endoscopy by premedication to subjects with 5 mg diazepam. There were very wide variations in change in DSST score. However we could not identify the independent variables that best predicted DSST score difference in a multiple regression analysis for age, plasma albumin level, and plasma diazepam concentration 30 min after intravenous administration. We should pay attention to patients' individual states in cognitive performance following gastrointestinal endoscopy after single-dose diazepam.
The xanthine oxidase (XOD) inhibitory activity of propolis from China and Brazil was measured. The propolis from both place were seen to have XOD inhibitory activity. However, a stronger tendency was shown in the propolis from China. The compounds in each the propolis were measured quantitatively. A great deal of chrysin, galangin, and caffeic acid phenetyl ester were found in the propolis from China, an abundance of p-coumaric acid and artepillin C in the propolis from Brazil. Therefore it was revealed that the propolis compounds are very different depending on their place of origin. The XOD inhibitory activity of these five compounds was measured. Caffeic acid phenetyl ester had the strongest activity, with chrysin and galangin next; p-coumaric acid and artepillin C showed weak XOD inhibitory activity. We evaluated the hypouricemic effect of propolis from China on hyperuricemia induced by the uricase inhibitor, oxonic acid (500 mg/kg p.o., 1 h before the test drugs), and measured plasma uric acid values in rats. Oral propolis had a hypouricemic effect 2 h after its administration to oxonate-pretreated rats. These results suggested that a continuous intake of propolis may be effective for the prevention and the treatment of gout and hyperuricemia.
A method has been proposed for determining the detection limit (LD) from the slope of a semilogarithmic plot of a B/B0 curve in competitive enzyme linked immunosorbent assay (ELISA). As an application, this paper describes a graphic determination of LD from analogue data in the literature. The LD obtained corresponds to the concentration at which the relative standard deviation of concentration estimates is 30%.
Rhamnose-binding lectins are widely found in fish eggs. However, their biologic effects on cultured cells are still unknown. Since catfish (Silurus asotus) egg lectin (SAL) bound to globotriaosylceramide (Gb3) expressed on the surface of cells, we analyzed the relationship between Gb3 expression and SAL binding in tumor cell lines using Raji, Daudi, ACHN, P388, and K562 cells. Gb3 was highly expressed on Raji cells but not on K562 cells. SAL bound abundantly to Raji cells but not to K562 cells, and SAL binding depended on the amount of Gb3 on the cell surface. SAL caused a reduction in cell size and increased annexin-V binding to and propidium iodide (PI) incorporation into Raji cells. Although this effect on Raji cells might represent damage at the late apoptosis or necrosis stage, SAL-treated Raji cells remained alive. Thus SAL enhanced PI incorporation into Raji cells without induction of cell death. We examined whether the effects of chemotherapeutic agent(s) are influenced by SAL. SAL increased the incorporation of doxorubicin (Dox) into Raji cells and consequently enhanced the cytotoxic effects of Dox. These results indicate that SAL may induce cell permeability without cytotoxity.