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YAKUGAKU ZASSHI, 130(6),769-775, 2010
Signal-transducing adaptor protein-2 (STAP-2) was recently identified as a novel adaptor protein and is a family of STAP adaptor protein and has a variety of functions in cellular signal transductions. Especially STAP-2 has a crucial role in immune systems by controlling cytokine signal transduction. STAP-2 functionally interacts with STAT3 through its YXXQ motif and enhances STAT3 transcriptional activation. In contrast, STAP-2 interacts with STAT5 through its PH and SH2-like domains and decreases STAT5 activity. Importantly, STAP-2 also binds to MyD88 and IKK-α/β and regulates LPS/TLR4 signaling. Moreover, STAP-2 interacts with Epstein-Barr virus-derived LMP1 and modulates LMP1-mediated NF-κB signaling. More importantly, experiments using STAP-2 deficient mice showed that STAP-2 modulated several T-cell functions. T-cells from STAP-2 deficient mice showed enhanced integrin-mediated cell adhesion to fibronectin. Furthermore STAP-2-deficient T-cells show reduced chemotaxis toward SDF-1α. These accumulated evidences indicate that novel adaptor protein STAP-2 plays an important modulator role in both of innate and adaptive immune systems.
Key words--signal-transducing adaptor protein-2 (STAP-2); adaptor protein; cytokine; signal transduction; immune system
YAKUGAKU ZASSHI, 130(6),777-784, 2010
Vascular tone is tightly regulated by endothelium-derived factors. These include relaxing factors (EDRFs) such as nitric oxide (NO), hyperpolarizing factors (EDHFs), and contracting factors (EDCFs). Although EDHF is a prominent vasodilator, particularly in smaller arteries, little attention has been paid to the potential role of EDHF responses in diabetes. EDHF signaling may involve various factors, including several diffusible factors and non-diffusible factors (e.g., gap junctions). It has been demonstrated that the alterations in EDHF relaxation seen in mesenteric arteries from diabetic rats may be attributable to an increase in phosphodiesterase 3 (PDE3) activity, leading to a reduction in the action of adenosine 3',5'-cyclic monophosphate (cAMP), and consequently the activity of protein kinase A (PKA) is decreased in such arteries. Moreover, it has been suggested that the imbalance between EDRFs and EDCFs is present in mesenteric arteries from type 2 diabetic rats and the EDHF relaxation can be partly reversed by suppression of EDCF signaling. Indeed, chronic treatment with metformin, eicosapentaenoic acid, or thromboxane synthase inhibitor can reduce EDCF signaling and normalize EDHF signaling in mesenteric arteries from type 2 diabetic rats. Although the improvement or restoration of EDHF responses has not been the direct subject of any pharmaceutical effort, increasing cAMP/PKA signaling (e.g., by inhibiting PDE3 activity) or reducing EDCFs signaling has potential as an interesting therapeutic target in diabetic vasculopathy.
Key words--endothelium-derived hyperpolarizing factor; endothelial dysfunction; diabetes; adenosine 3',5'-cyclic monophosphate; endothelium-derived contracting factor; prostanoids
YAKUGAKU ZASSHI, 130(6),785-791, 2010
Eighty percent (80%) aqueous acetone extract from fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-α (TNF-α)-induced death of hepatocytes, and the following structural requirements were suggested: i) the amide moiety was essential for strong activity; ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effect at a dose of 5 mg/kg, p.o. and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-α.
Key words--medicinal food; Piper chaba; hepatoprotective activity; TNF-α sensitivity degradation activity; piperine; amide constituent
YAKUGAKU ZASSHI, 130(6),793-800, 2010
Production, formulation and characterization of proteins play a major role in biotechnology industries. We have shown that aqueous arginine solution increases the solubility of proteins in formulation and purification, suppresses aggregation during refolding and storage and improves performance of column chromatography. Acidic arginine solution now finds application for virus inactivation. I will summarize these various effects of arginine on proteins and viruses and describe the current knowledge of the mechanism of the effects of arginine.
Key words--arginine; chromatography; solubilization; formulation; aggregation; weak interaction
YAKUGAKU ZASSHI, 130(6),801-804, 2010
5-Fluorouracil-loaded N-succinyl-chitosan nanoparticles (5-FU-Suc-Chi/NP) were prepared by emulsification solvent diffusion. Biodistribution and tumor targeting were evaluated after i.v. administration of 5-Fu-Suc-Chi/NPs in Sarcoma 180-bearing mice. Also, pharmacokinetic profiles were evaluated after intravenous injection of 5-Fu-Suc-Chi/NP via the tail vein to rats. Our experimental results showed the 5-FU-Suc-Chi/NPs could be sustained at a high level in the blood for a very long time, implying its long systemic retention in the circulation. 5-FU-Suc-Chi/NPs were distributed mainly in tumors and liver, with small quantities being found in kidney and spleen. 5-FU-Suc-Chi/NPs accumulated only slightly in the heart and lung, and lowered the toxic effect of 5-FU in the heart and lung. Pharmacokinetic analysis in plasma showed the area under plasma concentration-time curve (AUC), elimination half-life (t1/2), and residence time (MRT) were increased 2.5-fold, 10.98-fold, and 10.8-fold for 5-FU-Suc-Chi/NP compared with that of free 5-FU, respectively. These results indicate that a long half-life in the circulation and tumor targeting of 5-FU-Suc-Chi/NPs are possible.
Key words--N-succinyl-chitosan; nanoparticle; biodistribution; pharmacokinetic; tumor targeting
YAKUGAKU ZASSHI, 130(6),805-820, 2010
In recent years soaring medical costs have become a major social problem in developed countries. Ambulatory blood pressure (ABP) measurements have a stronger predictive power for cardiovascular events than clinic blood pressure (CBP) measurements. Therefore the introduction of ABP measurement for the diagnosis and treatment of hypertension should lead to a decrease in medical expenditure. This study presents calculations of the cost saving and life years associated with changing from CBP to ABP measurement as diagnostic tool. We constructed a Markov model using data from the Ohasama study and a Japanese national database. Study population was 7.042 million individuals aged 40 years and above living in Japan. The introduction of ABP for hypertension would result in a reduction of about 9.48 trillion yen per 10 years. We conducted a sensitivity analysis and found that the introduction of ABP was associated with at least a cost reduction of 47500 billion yen. But it did not provide significant extension of average life years. However the introduction of ABP for hypertension treatment would be a very effective method in perspective of public health because it reduced about 59600 individuals of stroke and about 18900 individuals of death. Given its cost-effectiveness, extensive application of ABP measurement in clinical practice is expected.
Key words--cost-effectiveness; hypertension; ambulatory blood pressure; Ohasama study
YAKUGAKU ZASSHI, 130(6),821-831, 2010
It is very important for students to undergo early exposure in 6-year pharmaceutical education; through this experience they will understand roles of pharmacists, map out their future career, and increase their motivation for learning. Therefore we had newly recruited pharmacists provide an early exposure program in a hospital. According to the results of a questionnaire survey involving students, educational staff of the Faculty of Pharmaceutical Sciences and the new pharmacists, 99% of the students were satisfied with the program, and their motivation for learning was enhanced. Interestingly, they were more careful regarding their grooming and appearance after completing the program. Educational staff of the Faculty of Pharmaceutical Sciences evaluated the new pharmacists and their teaching very positively, and, in turn, the pharmacists assessed an early exposure program in a hospital as significant. Therefore we conclude that the system for early exposure was useful for both students and new pharmacists.
Key words--early exposure program in a hospital; hospital work; new hospital pharmacist; pharmacy student; questionnaire survey
YAKUGAKU ZASSHI, 130(6),833-840, 2010
Propolis is known to have abundant bioactive constituents and a variety of biological activities. To investigate the effect of Brazilian propolis on insulin resistance, 10-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a non-insulin-dependent type 2 diabetic model, were treated for 4 weeks with propolis (100 and 300 mg/kg, p.o.) or vehicle (control). Propolis treatment significantly decreased the plasma levels of insulin and insulin resistance index (Homeostasis Model Assessment-Insulin Resistance; HOM-IR), without affecting blood glucose levels and tended to lower systolic blood pressure compared with the control. In isolated and perfused mesenteric vascular beds of OLETF rats, propolis treatment resulted in significant reduction of sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS) and tended to increase calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS compared with in vehicle-treated OLETF rats. However, propolis treatment did not significantly affect the vasoconstrictor and vasodilator response to noradrenaline, CGRP, acetylcholine, and sodium nitroprusside. These results suggest that propolis could be an effective and functional food to prevent development of insulin resistance.
Key words--propolis; insulin resistance; Otsuka Long-Evans Tokushima Fatty rat; periarterial nerve function; mesenteric vascular bed
YAKUGAKU ZASSHI, 130(6),841-846, 2010
Hypercholesteremia is one of the risk factors for coronary artery disease. The present study highlights the efficacy of the ayurvedic herbal formulation Arborium Plus [Hyppophae ramnoides L. fruit juice (S) and Rhododendron arboreum Sm. Linn flower juice (R) in a 1:4 ratio] on triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), atherogenic index (AI), high-density lipoprotein (HDL), and high-sensitivity c-reactive protein (hs CRP) in experimentally induced hypercholesterolemic rabbits. Four groups of rabbits were subjected to different treatments for 8 weeks: control group, CHOL group (1% w/w cholesterol for 8 weeks), S+R group (1% w/w cholesterol and Arborium Plus for 8 weeks), and A group (1% w/w cholesterol and atorvastatin for 8 weeks). The results showed significant increases in TG, TC, LDL, AI, and hs CRP in hypercholesterolemic rabbits which was significantly reduced in Arborium Plus-treated hypercholesterolemic rabbits. The data demonstrated that the Arborium Plus formulation was associated with hypolipidemic effects in experimentally induced hypercholesterolemic rabbits.
Key words--hyperlipidemia; Oil Red O; sea buckthorn; Rhododendron; atherogenic index; c-reactive protein
YAKUGAKU ZASSHI, 130(6),847-855, 2010
Neurotoxicities of dibutyltin (DBT), tin(II) octylate (OT), poly-L-lactides (PLLA, molecular weight [MW]=5000, PLLA 5000), PLLA without tin (MW=3000, PLLA 3000), PLLA with a large amount (590 ppm) of tin (S3), poly(glycolic acid-co-ε-caprolactone) oligomer (MW=6200, PGC oligomer), and poly(L-lactic acid-co-glycolic acid-co-ε-caprolactone) oligomer (MW=6400, PLGC oligomer) related to artificial dura mater were examined using the murine astrocyte cell line, CRL-2534. The indices were cell viability, glutamate concentration in the cell supernatant, and cell proliferation. Lower cell viability was observed among cells exposed to 0.5 μM DBT or 10 μg/ml of S3. There were no differences in cell viability of astrocytes exposed to OT, PLLA 5000, PLLA 3000, PGC oligomer, or PLGC oligomer. Mean glutamate concentration in the supernatant of cells exposed to 0.25 μM DBT was higher than that of the control after 2 h incubation. Lower mean concentration of glutamate in the supernatant of cells exposed to 5 μg/ml of S3 was observed after 2 h incubation. Cells exposed to 50 μg/ml of PGC oligomer had a higher mean concentration of glutamate in the supernatant. OT only inhibited cell proliferation at 100 μM. Proliferation of cells exposed to 0.25 μM or 0.5 μM DBT was inhibited, as was that of cells exposed to 100 μM OT, 50 μg/ml PLLA 5000, 50 μg/ml PLLA 3000, and 5 μg/ml S3, 5 d and 7 d after exposure. Although DBT does not reach levels that induced neurotoxicity in artificial dura mater, these results suggest that DBT is neurotoxic and PLLA toxicity increases with the increase in tin concentration.
Key words--neurotoxicity; dibutyltin; astrocyte; artificial dura mater; poly-L-lactide; tin(II) octylate
YAKUGAKU ZASSHI, 130(6),857-866, 2010
Over recent years, use of self-medication by patients to help prevent and treat their own medical conditions has become increasingly widespread. However, despite provision of warnings and the taking of precautions, health hazards due to medication have occurred and continue to occur. In order to ward off such incidents, it is necessary for both children and adults to be educated about appropriate drug use. And, it is desirable that pharmacy students participate in this medicinal education as a means of affirming what they have learned and improving their communication skills at an early stage in their professional development. In 2008, we held medicinal education classes for pupils and parents at three elementary schools in Aichi Prefecture with the aim of promoting appropriate drug use. Each class comprised of two parts: an introductory lecture in quiz form, lasting about 30 minutes, and a 30-minute participatory group experiment. Subsequently, the activities carried out in both parts were evaluated across 6 items and 3 items respectively, and scored from Satisfied to Unsatisfied (4-step scale) by the pupils and their parents. We also conducted a questionnaire survey on this activity to the pharmacy students. We achieved successful results, gaining high Satisfied levels (better than 90%) in all items. This activity benefited both the children and the pharmacy students. It not only provided education for the general public regarding the appropriate drug use, but is also helping to foster the development in Japan of well-trained future pharmacists.
Key words--medicinal education; pharmaceutical education; medicine class; appropriate drug use
YAKUGAKU ZASSHI, 130(6),867-871, 2010
Optimization of benzalkonium chloride (alkyl dimethylbenzylammonium chloride: BAK) concentration as preservative in 0.0015% tafluprost ophthalmic solution (Tapros® 0.0015% ophthalmic solution), an anti-glaucoma medicine, was examined from the points of ocular surface safety and preservative efficacy. BAKC12, which is dodecyl dimethylbenzylammonium chloride, and BAKmix, which is the mixture of dodecyl, tetradecyl and hexadecyl dimethylbenzylammonium chloride were used in this study. The effects of BAKC12 concentrations and the BAK types, BAKC12 and BAKmix, in tafluprost ophthalmic solution on ocular surface safety were evaluated using the in vitro SV 40-immobilized human corneal epithelium cell line (HCE-T). Following treatments of Tafluprost ophthalmic solutions with BAKC12, its concentration dependency was observed on cell viability of HCE-T. The cell viability of HCE-T after treatment of these solutions with 0.001% to 0.003% BAKC12 for 5 minutes were the same level as that after treatment of the solution without BAK. Tafluprost ophthalmic solution with 0.01% BAKC12 was safer for the ocular surface than the same solution with 0.01% BAKmix. Preservatives-effectiveness tests of tafluprost ophthalmic solutions with various concentrations of BAKC12 were performed according to the Japanese Pharmacopoeia (JP), and solutions with more than 0.0005% BAKC12 conformed to JP criteria. It was concluded that 0.0005% to 0.003% of BAKC12 in tafluprost ophthalmic solution was optimal, namely, well-balanced from the points of ocular surface safety and preservative efficacy.
Key words--ocular surface safety; preservative efficacy; benzalkonium chloride; preservative; tafluprost; anti-glaucoma medicine
YAKUGAKU ZASSHI, 130(6),873-879, 2010
A simple and specific high-performance liquid chromatographic (HPLC) method was developed for the pharmacokinetic study of hyperoside (HP, isolated from the leaves of Crataegus pinnatifida Bge. var. major) in rats after intravenous administration. The plasma samples were deproteinized with methanol after addition of internal standard (I.S.), baicalin. HPLC analysis was performed on a Diamonsil C18 analytical column, using methanol-0.6% aqueous phosphoric acid (45:55, v/v) as the mobile phase with UV detection at 340 nm. The calibration curve was linear over the range of 0.8921-59.7125 μg/ml in rat plasma. The average extraction recovery of HP was 99.33±0.86%, and the relative standard deviations (R.S.D.s) of the intra- and inter-day precisions were no more than 7.8 and 2.5%, respectively. The lower limit of quantification (LLOQ) was 0.8921 μg/ml. The validated method was successfully applied during a pharmacokinetic study in rats after intravenous administration of HP at different doses, and all the results indicated that the pharmacokinetics of HP in rats obeyed nonlinear processes.
Key words--hyperoside; pharmacokinetics; HPLC; rat plasma
YAKUGAKU ZASSHI, 130(6),881-887, 2010
In this study, to clarify the characteristics of a migraine screener that would be useful to pharmacists in community pharmacies, we used the migraine screener to investigate patients with migraine. Diagnosis of migraine was made according to the internal classification of headache disorders 2nd edition (ICHD-II). Eighty patients with migraine (with aura: n=21, without aura: n=59) were divided into a positive group (n=51, 64%) and a negative group (n=29, 36%) based on the results of the migraine screener, which included a 4-item (headache exacerbation in daily performance, nausea, light-sensitivity and hypersensitivity to odors). The positive rate of the migraine screener was 64%. In the positive group, patients had moderate-to-severe migraine attacks in the past 3 months. Moreover, 82% of patients in the positive group reported disturbances in their daily of life due to headache. In the negative group, 41% of patients also reported disturbances in their daily of life. Therefore, pharmacists have to check the influence of headache on daily of life not only in the positive group but also in the negative group. These findings provide useful information to guide pharmacists in community pharmacies when using the screener for migraine to distinguish patients with headache from those with migraine.
Key words--migraine; screener; pharmacist
YAKUGAKU ZASSHI, 130(6),889-893, 2010
The formation of an inclusion complex of amoxicillin (AMX) with β-cyclodextrin (β-CD) in aqueous solution was confirmed by a solubility method and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The apparent stability constant for the inclusion complex was 10.72 M−1 in water at 25°C. The effect of α-CD, β-CD, and γ-CD on the degradation of AMX in a pH 1.2 solution at 37°C was investigated. β-CD and γ-CD reduced the rate of degradation. α-CD had no effect. These results were consistent with those of 1H-NMR spectroscopy. The effect of β-CD on the degradation rate was studied in more detail. The apparent first order rate constant for the degradation of AMX in the pH 1.2 solution at 37°C was 0.1121 h−1 (t1/2=6.18 h), which decreased with the addition of β-CD. The rate constants and t1/2 values for the concentrations of β-CD added, corresponding to molar ratios of AMX to β-CD of 1:0.5, 1:1, 1:2, 1:5, and 1:10, were 0.1051 h−1 and 6.59 h, 0.0992 h−1 and 6.98 h, 0.0893 h−1 and 7.76 h, 0.0697 h−1 and 9.95 h, and 0.0509 h−1 and 13.61 h, respectively. The activation energy for the degradation of AMX in the pH 1.2 solution was increased from 6.9×104 J/mol (AMX alone) to 8.0×104 J/mol (AMX:β-CD=1:10).
Key words--amoxicillin; β-cyclodextrin; inclusion complex; stability; acidic solution
YAKUGAKU ZASSHI, 130(6),895-902, 2010
Candidiasis is a common opportunistic fungal infection that responds well to amphotericin B (AMPH) treatment. However, AMPH often causes adverse effects such as kidney injury and hypokalemia. Because some essential oils have been reported to have antifungal effects, we investigated the antifungal activity of various essential oils and their major constituents against Candida spp. Most essential oils examined in this study showed antifungal activity, and several enhanced the antifungal effect of AMPH. Clove oil in particular, and its major constituent eugenol, had potent effects. These findings suggest that combining certain essential oils or their constituents with AMPH may be useful for suppressing the adverse effects of AMPH treatment.
Key words--Candida; amphotericin B; essential oil; clove oil; eugenol; antifungal effect
YAKUGAKU ZASSHI, 130(6),903-910, 2010
Many healthcare workers are concerned about the risk of occupational exposures to hazardous drugs. The Japanese Society of Hospital Pharmacists (JSHP) revised the “Guidelines for the Handling of Antineoplastic Drugs in Hospitals”, however, the precautions and awareness of handling drugs varied in institutions. We assessed the levels of environmental contaminations in our hospital and urinary excretion of cyclophosphamide (CP) and ifosfamide (IF) in pharmacists and nurses. In environmental studies, we obtained samples by wiping the surfaces around two biological safety cabinets (BSCs) on eight days for four months. One BSC was equipped in hospital pharmacy and the other was equipped in an oncology ward, and used for preparing chemotherapeutic drugs for outpatients and for inpatients, respectively. We obtained the urine samples from 6 pharmacists and 2 nurses. We used solid phase extraction (SPE) as a convenient extraction procedure and liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) for the analysis of the samples. CP was detected on the working surfaces inside both BSCs, and detected at low levels on the back surfaces of the BSCs and at the working tables around the BSCs. IF over the LLOQ was not detected in both BSCs. CP and IF were not detected in all urine samples of pharmacists and nurses. Detection frequencies and amounts of these drugs were low levels, compared with previous reports in Japan, and our results showed that improving awareness about handling hazardous drugs could reduce the risk of the occupational exposures.
Key words--cyclophosphamide; occupational exposure; environmental contamination; solid phase extraction; liquid chromatography/mass spectrometry/mass spectrometry
YAKUGAKU ZASSHI, 130(6),911-916, 2010
Bedsides conventional bedside training the Department of Pharmacy of Kyushu University of Health and Welfare covers advanced practices focused on new procedures expected for future pharmacists. A questionnaire survey was conducted among the 4th year students of the 6-year curriculum of the department in order to retrospectively evaluate their attitudes toward basic life support, and the necessity and feasibility of items related to the training. Sixty-nine percent of the students responded that they would provide appropriate treatment under a situation where basic life support was needed. The item regarded as most necessary and feasible before training was “treatment for basic life support—cardiopulmonary resuscitation.” After training, however, “checking vital signs,” “physical assessment,” and “pharmacist's assistance in medication” were the items rated as equal to or higher than “treatment for basic life support—cardiopulmonary resuscitation.” The lowest ranked item in terms of necessity and feasibility both before and after training was “intramuscular/subcutaneous injection,” followed by “intravenous injection” and “normal intravenous collection of blood” in that order. The results of this attitude survey demonstrated that many students were willing to perform such operations as part of checking vital signs and physical assessment.
Key words--vital sign; physical assessment; basic life support; cardiopulmonary resuscitation; bedside training; attitude survey