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YAKUGAKU ZASSHI, 125(8),601-615, 2005
Cells, which are the basic unit of life, are the most intelligent particles on earth. Recent advances in life science research encourage the development of cell therapy utilizing specialized functions of highly differentiated cells, the self-renewal and differentiation abilities of stem cells, and signal networks among various types of cells. Although cell therapy including ex vivo gene therapy, cellular immunotherapy, and regenerative therapy is expected to become the next generation of medical care for intractable disorders, the establishment of technology to prepare cells as medical supplies, namely, cytomedicine, is essential for the assurance of efficacy and safety in cell therapy. This review introduces our approach to the design and creation of cytomedicine for application to cell therapy against diabetes mellitus and cancer.
Key words--cytomedicine; cell therapy; APA-microencapsulation; dendritic cell-based immunotherapy; cell delivery systems
YAKUGAKU ZASSHI, 125(8),617-629, 2005
Oxidized low-density lipoprotein (Ox-LDL) is known to be involved in the generation and progression of atherosclerosis. Ox-LDL has a number of potentially atherogenic effects on vascular cells, including uncontrol uptake by scavenger receptors. Asp-hemolysin, a hemolytic toxin from Aspergillus fumigatus, is a binding protein for Ox-LDL. This study was undertaken to clarify the binding specificity of Asp-hemolysin to Ox-LDL. We examined the binding specificity of Asp-hemolysin to Ox-LDL using several modified lipoproteins and scavenger-receptor ligands. Asp-hemolysin bound to Ox-LDL with shorter LDL oxidation times. However, Asp-hemolysin did not bind to acetylated LDL. The native high-density lipoprotein (n-HDL) and modified HDL (e.g., acetylated HDL, oxidized HDL) also had no Asp-hemolysin binding. Inhibitors of scavenger-receptor binding, including maleylated bovine serum albumin, polyinosinic acid, dextran sulfate, and fucoidin, had no effect on the binding of Ox-LDL to Asp-hemolysin. Surface plasmon-resonance studies revealed that Ox-LDL binds with high affinity (KD=0.63 μg/ml) to Asp-hemolysin. Furthermore, we have shown that Ox-LDL strongly inhibits the hemolytic activity of Asp-hemolysin and that the removal of lysophosphatidylcholine (lysoPC) from Ox-LDL abolished the inhibition. We also investigated the interaction between Asp-hemolysin and lysoPC as a typical lipid moiety of Ox-LDL. The binding of Asp-hemolysin to LDL oxidized for different times depended on the lysoPC content in each Ox-LDL. In addition, the inhibition of lysoPC production in Ox-LDL by phenylmethylsulfonyl fluoride (PMSF) pretreatment of LDL resulted in a marked decrease in Asp-hemolysin binding to PMSF-pretreated Ox-LDL. The binding analysis of Asp-hemolysin to lysoPC revealed that Asp-hemolysin binds directly to lysoPC. We conclude that Asp-hemolysin is a specific binding protein with high affinity for Ox-LDL and that its binding specificity is distinct from any receptor for Ox-LDL.
Key words--Asp-hemolysin; oxidized low-density lipoprotein (Ox-LDL); lysophosphatidylcholine (lysoPC); binding specificity
YAKUGAKU ZASSHI, 125(8),631-637, 2005
Therapeutic drug monitoring (TDM) is widely applied to a variety of medications, including antibiotics, immunosuppressants, and antidepressants, but the clinical utility of TDM for anticancer agents is currently limited by several factors. The primary reason is the poorly-defined concentration-effect relationships for most anticancer drugs. TDM has the potential to improve the clinical use of anticancer agents. This paper reviews the relations between the pharmacokinetics of a new anticancer agent, amrubicin, and the clinical response and toxic side effects in patients. The plasma concentration of amrubicin peaked immediately after a bolus intravenous injection of the drug and declined in a biexponential manner thereafter, whereas that of C-13 hydroxy metabolite amrubicinol also peaked just after amrubicin injection but decreased more gradually compared with that of amrubicin. The apparent total clearance of amrubicin showed a large interindividual variability, despite adjustment of dosage for body surface area. Leukocytopenia of grades 3 or 4 occurred in most patients, and thrombocytopenia and anemia of grades 3 or 4 were also common. Since the area-under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematological toxicities, it is thought that the plasma concentration of amrubicin and amrubicinol may provide useful information for establishing the optimal dosage of amrubicin in each patient.
Key words--amrubicin; amrubicinol; therapeutic drug monitoring
YAKUGAKU ZASSHI, 125(8),639-642, 2005
To obtain revised information on drug package inserts, we evaluated the quality and comprehensibility of such information provided by the Web site of the Pharmaceuticals and Medical Devices Agency (PMDA site), medical representatives (MRS), Drug Safety Updates (DSUS), and informational publications of the wholesale distributor Company F (wholesaler F). In the comparison of the total amount of revised information obtained from April 2003 to March 2004, the PMDA site was 90% or greater of comprehensible. In comparison with the distribution information on the notice of the Ministry of Health, Labor and Welfare, an informational delay or lack occasionally occurred and variations among pharmaceutical companies were observed. Moreover, on the PMDA site, the number of revisions was 1972. Among them, clinically important information, such as warnings, contraindications, adverse effects, and drug interactions, totaled 37%. From these results, it is suggested that there are variations in the information from each pharmaceutical company on the PMDA site although the site is excellent in terms of comprehensibility.
Key words--package insert; drug information; adverse reaction; drug interaction
YAKUGAKU ZASSHI, 125(8),643-652, 2005
The estrogenic activities of ultraviolet absorbers and their related compounds were investigated using MCF-7 cell proliferation assay. Nine of 33 chemicals (benzophenone, 2,4-dihydroxybenzophenone, 2,2',4,4'-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 4-hydroxybenzophenone, 3-(4-methylbenzylidene) camphor, ethyl 2-cyano-3,3-diphenylacrylate (etocrylene) and 2-ethylhexyl-2-cyano-3,3-diphenylacrylate (octocrylene)) were positive compared with the vehicle control. Benzhydrol, ethyl cinnamate and 2,2'-dihydroxy-4-methoxybenzophenone were weakly active. When each xenoestrogen was added to the cells along with ICI 182780, an estrogen receptor (ER) antagonist, the cell growth was reduced according to its doses. Therefore, the cell proliferation was suggested to generate through ER. Most of these chemicals were also positive using CHOOSER assay, a new method of testing estrogenic activity of xenoestrogen. Each xenoestrogen was also confirmed to bind to ERα and ERβ using a human ER competitive binding assay against 17β-estradiol. The concentration order of the strength of its inhibitory effect using both ERα and ERβ was similar to that of MCF-7 cell proliferation assay, except for benzyl 4-hydroxybenzoate (B4HB). B4HB showed a stronger activity on CHOOSER assay and the competitive binding assay using both ERα and ERβ, although there was no activity observed on MCF-7 cell proliferation assay. Our findings were to detect the estrogenic activity of etocrylene and octocrylene in vitro, in addition to confirming the activities of some ultraviolet absorbers as previously reported.
Key words--UV absorbers; estrogenicity; etocrylene; octocrylene; MCF-7 cells; competitive binding assay
YAKUGAKU ZASSHI, 125(8),653-657, 2005
The effects of losartan potassium, an angiotensin AT1 receptor blocker on immobility in forced swim test have been studied. Effect of losartan potassium, nortriptyline HCl, fluoxetine HCl and reserpine per se and in combination on forced swimming-induced immobility in mice have also been studied. In mice, losartan potassium elicits biphasic responses i.e. positive responses at lower doses (0.1, 1.0 and 5 mg/kg, i.p.) in the forced swim test, a test of potential antidepressant activity and vice versa at higher dose (20 and 100 mg/kg, i.p.). In chronic studies, enhancement in immobility was observed for losartan potassium (3 and 30 mg/kg, p.o., 21 days). In acute combination studies, losartan potassium (1 and 5 mg/kg) significantly reversed the reserpine-induced immobility, but vice versa at 100 mg/kg. Losartan potassium (0.1 and 5 mg/kg) potentiate antidepressant activity of nortriptyline (30 mg/kg, i.p.) in mice, but vice versa at 100 mg/kg. Likewise, Losartan potassium (100 mg/kg), significantly reversed antidepressant activity of fluoxetine HCl, but at 0.1 and 5 mg/kg, failed to modify fluoxetine HCl induced immobility. The obtained biphasic effect of losartan potassium on immobility in mice might be due to inhibitory effect on AT1 receptor at lower dose and pronounced effect on AT2 receptor at higher dose (large concentrations of losartan potassium can displace Angiotensin II (Ang II) from its AT1 receptor to AT2 receptor.
Key words--forced swim test; immobility time; losartan potassium; reserpine; nortriptyline; fluoxetine
YAKUGAKU ZASSHI, 125(8),659-663, 2005
The aim of this study was to assess whether Marrie's critical pathway is an effective approach to reduce the duration of antibiotic intravenous therapy and drug cost in patients with community-acquired pneumonia (CAP) in Japan. We conducted a retrospective cohort study in patients with CAP who were admitted to a community hospital or a university hospital. We collected clinical and economic data from medical records and medical fee receipts and estimated drug cost for switching the dosage form using Marrie's critical pathway. Outcomes of this study were change in duration of intravenous therapy and drug cost. Fifty patients with CAP were selected from two hospitals. Actual days of antibiotic intravenous therapy were 9.5±4.2 days; in contrast, estimated days were 1.2±3.0 days (p<0.001). Actual drug cost was 37148±28791 yen; in contrast, estimated drug cost was 8364±18356 yen (p<0.001). Average reduction of days of therapy and drug cost were 8.3 days and 28704 yen, respectively. This study suggests that the implementation of Marrie's critical pathway may be an effective approach to reduce medical resources used for CAP treatment in Japan.
Key words--economic analysis; cost saving; critical pathway; community-acquired pneumonia
YAKUGAKU ZASSHI, 125(8),665-670, 2005
To study the antitumor activity of alkaloid extracted from Oxytropis ochrocephala and its possible mechanism, we observed the effect of alkaloid on tumor weight and expression of PCNA and p53 in mice bearing H22 hepatocellular carcinoma by means of immunohistochemistry SP method. After treatment with alkaloid from Oxytropis ochrocephala, the results showed that alkaloid administration (25 and 50 mg/kg body weight, p.o.) could inhibit H22 hepatocellular carcinoma growth to various extent, and the rates of inhibition were 48.5% and 57.7% respectively (p<0.01). The antitumor activity of the alkaloid is in a dose dependent manner, with no signs of toxicity to weight, kidney and liver. The sections of tumor showed the number of tumor cell decreased and nucleus appeared putrescence such as nucleus atrophy, disintegrating and dissolving. Meanwhile, the expression of PCNA and mutant p53 protein positive cell numbers in mice bearing H22 hepatocellular carcinoma also suppressed by alkaloid (p<0.05). It suggested that Alkaloid from Oxytropis ochrocephala showed antitumor effect and its possible mechanism might be associated with the expression inhibition of PCNA and mutant p53 protein. Further studies are needed to explore the antitumor activity of the other compounds of Oxytropis ochrocephala and to specify their possible mechanism of action.
Key words--antitumor activity; Oxytropis ochrocephala; alkaloid; PCNA; mutant p53 protein; H22 hepatocellular carcinoma