Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three anzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.
Vitamin D (D) plays important roles for homeostasis of serum calcium and so on, in human after metabolic activation. The measurements of concentrations of D metabolites in biological fluids are important for clinical and nutritional diagnoses. In these respects, developments of analysis of D metabolites, especially the phase I reaction products (free metabolites), have been carried out. In the first part of this report, the advance in developments of analysis of the free metabolites is reviewed according to the methodology over the last five years. The phase II reaction products (conjugated metabolites) of D, which are poorly understood compared to the free metabolites, are recently found in many kinds of animals, and much interest is focused on their physiological roles. In the second part, an overview of the identification and quantification of the conjugated D metabolites in biological fluids is presented mainly from our studies.
We quantitatively studied factors influencing the environment cleanness for intravenous hyperalimentation (IVH) admixing. The environment cleanness was evaluated by measuring the counts of particles (>0.5μm) and bacteria floating in 1 ft3 of the air inside the clean room (23.6m3) and in the clean bench built in the department of pharmacy, The University of Tokyo Hospital in 1998. The number of particles at the center of the clean room during IVH admixing by 4 pharmacists was higher than that at the medicine passing area (150±50/ft3 vs. 260±60/ft3; mean±S.D., n=12). The cleanness inside the clean room was improved as the measurement point became higher from the floor (600±180/ft3, 150±50/ft3, and 35±15/ft3 at 50, 100, and 150 cm height, respectively) and the number of persons working inside the room decreased. The changes in the counts of floating bacteria were similar to that of floating particles under the same conditions. In addition the effect of disinfection on the counts of bacteria was clearly observed. When the cleanness of the room became lower by turning off the air conditioning, the particle counts inside the clean bench became lower along with the distance from the front glass becoming deeper (i.e., 1400±550/ft3, 140±70/ft3, and 40±30/ft3 at 0, 5, and 15 cm, respectively). From these lines of evidence, the following items were suggested in order to maintain the environment cleanness for IVH admixing. First, the number of persons residing in the clean room should be kept to be minimum. Second, the clean bench should be set up in the center of the clean room. Finally IVH admixing operation should be performed at more than 15 cm depth inside the front glass surface of the clean bench. Moreover, the effect of mopping-up of the clean room with 0.1% benzethonium chloride clearly demonstrated the importance of disinfection on a routine basis.
Plastics has been widely used at the hospitals and dominates the field of the manufacture of infusion bag sets and packaging materials as a disposable product. Recently, it has been reported, however, that expected drug effects could not be obtained owing mainly to the drug adsorption to the surface of plastic bags observed when several injection drugs such as nitroglycerin, isosorbide dinitrate, diazepam, and insulin were injected mixedly into a certain plastic intravenous bags. And there is a possibility of the occurrence of chemical reactions between the added drugs and the surface of plastic bags. We also can not deny the possibility of the dissolution of softener from the plastic bags. On the other hand, we have been working on the nature of plasma treatment of polymer surfaces by irradiation of low temperature plasma and its pharmaceutical application studies. In this study, we obtained the data concerning the effect of plasma treatment on the reduction of adsorption of insulin to the surface of ethylene-vinylacetate (EVA) bag.
The effects of allopurinol (Allop) on the lipid peroxidation in the nephrotoxicity of an antitumor drug, cisplatin (CDDP) were studied in mice. CDDP was administered intraperitoneally to two groups (CDDP+Allop group and CDDP+CMC-Na group) at single doses of 10 mg/kg, and mice were sacrificed 3 days after CDDP administration. The body weights of the CDDP-administered group gradually decreased to approximately 78% of the values of the control group (saline+Allop group and saline+CMC-Na group) within 3 days. Plasma urea nitrogen and creatinine, especially in the CDDP+Allop group, increased after 3 days. Lipid peroxides in the blood and kidney were monitored by measuring the production of malondialdehyde (MDA), which increased in the CDDP+CMC-Na group. On the other hand, MDA levels in the CDDP+Allop group increased in the kidney but remained unchanged in the blood. Changes were observed in tissue glutathione (reduced form, GSH; oxidized form, GSSG) levels in the CDDP+Allop group but not in the CDDP+CMC-Na group. Histomorphological examination demonstrated the degeneration of the proximal tubuli in the CDDP-administered groups. Especially in the CDDP+Allop group, the increase of mesangium cells in the glomeruli was observed. From these results, it was suggested that Allop was not able to inhibit CDDP-induced lipid peroxidation in the kidney, and the kidney function became more severely impaired by the administration of Allop.
As a continuing study of chemical characterization of crude drug processing, we have been analyzing the chemical constituents in licorice roots before and after processing. At first, we analyzed chemical constituents in licorice roots of various origins. Next, we have developed the HPLC analytical method, by which saponins and flavonoids, major constituents in various licorice roots, were determined simultaneously in a quantitative manner. In this paper, by means of the HPLC analytical method, chemical constituents in licorice roots, processed and unprocessed, were determined. It was found that nonglycosidic flavonoid constituents were mostly lost while root bark removing, whereas, in roasted licorice roots, sugar chains in the saponin and glycosidic flavonoid constituents were hydrolyzed stepwise during roasting through hydrothermolysis.
The time courses of intensity changes of X-band electron spin resonance (ESR) spectra in the blood, liver, spleen, kidney and porta hepatis of rats were examined after 3-carbamoyl-2, 2, 5, 5-tetramethylpyrrolidin-1-yloxyl (carbamoyl-PROXYL) was perorally administered. The quenching activities of nitroxide radicals were determined using homogenate of the organs of individual rats. It was found that administrated nitroxide radicals were delivered to the liver, spleen, and kidney after peroral administration, where ESR signal intensities in the blood decreased gradually. The concentration of the elivered nitroxide radical varied with the individual organs. The quenching activity of the nitroxide radical for the homogenate of the porta hepatis was the highest before administration, while the concentration due to the reduced deoxidized-nitroxide radical compounds after 4 h of peroral administration was shown to be high in the kidney. It is concluded that the nitroxide radical compound is quenched in the porta hepatis of the liver, while the reduced nitroxide radical compound is delivered to the kidney.
Antifungal activity of medicinal plants against Aspergillus niger was evaluated using Bio-Cell Tracer (BCT). By this system enabled the real time determination of hyphal growth rate could be done in the presence or absence of Chinese herbal extracts. Of the 41 herbal extracts with 60% acetone extracts tested by the present method, 26 were found to contain active components against A. niger hyphal growth. In contrast, by conventional methods, no active component was detected from every herbal extract except 3 herbal extracts. From the extract of Anemarrhena asphodeloides, one of active components was isolated and its structure determined by NMR, UV, and mass spectroscopy. The compound was identified as broussonin A (2-3-(4-hydroxyphenyl)propyl)-5-methoxy-phenol) which was formerly reported as a phytoalexin of Broussonetia papyrifera VENT.
Utilities between patient drug information leaflets printed with photographs of medicines (Leaflet method) and medicine bags printed with the same content of the leaflet (Bag method) were compared and evaluated by a questionnaire to patients. Four hundred twenty eight and 401 questionnaires were returned for the bag method and for the leaflet one, respectively. Consequently, the reading frequency of the presented literature by the bag method was significantly higher than that by the leaflet method. The bag method was more effective than the leaflet method on the reading frequency among patients at the age 50's, whose reading frequency for the presented literature was thought to be lowest. Less than 20% of patients answered that missing to take medicine could be improved by patient drug information, while more than 50% of patients answered that they could learn the names and the effects of medicines from the patient drug information in any method. The bag method is useful to increase the reading frequency of the patients for the presented literature about drug information.
Ketamine is known to have distinguished analgesic effects without anesthetic when administered in a low dose. Since ketamine is not commercially available except injection forms, we prepared ketamine tablets for the home-care medication of patients with neuropathic pain. The direct compression or wet granulation method was employed to form 150 mg of tablets containing 50 mg of ketamine. The latter method was superior to the former one in terms of content uniformity, weight variation and disintegration tests of the tablets. Ketamine contents in the tablet prepared by the wet granulation method were unchanged for 12 weeks under the conditions of 25°C and 75% relative humidity (RH). The Cmax and AUC0-3h values for ketamine after administration of the tablet were slightly smaller than those of the syrup in a healthy volunteer. However, analgesic effects of the tablet was similar to that of the syrup in a patient with neuropathic pain. And the tablet was also effective for another four patients with neuropathic pain. These results indicate that ketamine tablets are useful for the home-care medication of patients with neuropathic pain.