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ISSN 1347-5231

Publications in this journal

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    ABSTRACT: This study aimed to determine how much time can be saved with the use of unit-of-use packaging for prescription drugs as compared with bulk packaging in community pharmacies as well as to determine the number of errors. In a simulation, mock prescriptions were dispensed either in unit-of-use packages or by transferring medication from a bulk container, and a time study was conducted to measure the time spent on dispensing and prescription auditing by pharmacists. Pharmacists' and patients' degree of satisfaction was also surveyed. The time saved with unit-of-use packaging was 66.25 seconds per prescription. The sole dispensing error that was found in the study occurred with bulk dispensing. Among both pharmacists and patients, many were of the opinion that dispensing with unit-of-use packaging was preferable to bulk dispensing. Unit-of-use packaging shortens the time that pharmacists spend on dispensing activities and increases the efficiency of their work. Unit-of-use packaging is also thought to reduce the number of counting errors.
    YAKUGAKU ZASSHI 04/2014; DOI:10.1248/yakushi.14-00013
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    ABSTRACT: Low-dose aspirin-induced gastrointestinal lesions are becoming an important problem in clinical practice. In our investigation of such adverse effects, we obtained 4 important findings considered useful for physicians, as follows; 1) even when aspirin was given at a dose, the incidence rate of gastrointestinal lesions was higher than with other NSAIDs, 2) the odds ratios for gastrointestinal lesions induced by aspirin with a histamine H2 receptor antagonist and proton pump inhibitor were 0.6 and 0.4, respectively, as compared with aspirin alone, 3) it is difficult to administer aspirin, which exerts an antiplatelet effect, without inducing gastrointestinal lesions, and 4) these gastrointestinal lesions appears early, especially within 2 years after administration. We distributed a questionnaire to 41 physicians to confirm our findings, and compared high (n=20) and low (n=21) frequency aspirin prescription groups. The recognition rate of points 1 and 3 noted above in the high group was significantly elevated as compared to the low group, whereas there no significant difference in regard to the information in point 4 between the groups and the rate of recognition was low. Moreover, only 27% of the surveyed physicians were familiar with all 4 points. Prior to receiving this information, 17% of the physicians gave no related instructions their patients, which was reduced to 0% after receiving this information. Furthermore, 98% of those surveyed found the information to be useful. Our results suggest that these 4 points of information regarding potential adverse gastrointestinal effects of low-dose aspirin are useful for physicians.
    YAKUGAKU ZASSHI 01/2014; DOI:10.1248/yakushi.13-00193
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    ABSTRACT: Effects of sucrose fatty acid esters (sugar esters) on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) with various molecular weights were used as model drugs of poorly absorbable drugs. The absorption of CF from the rat small intestine was significantly enhanced in the presence of various sugar esters and a maximal absorption enhancing effect was observed in the presence of 0.5%(w/v) S-1670. The absorption enhancing effect of S-1670 in the small intestine decreased as the molecular weights of drugs increased. Moreover, we evaluated the intestinal membrane damage with or without various sugar esters. These sugar esters (0.5%(w/v)) did not increase the activities of lactate dehydrogenase (LDH), suggesting that these sugar esters did not cause serious membrane damage to the intestinal epithelium. Furthermore, these sugar esters increased membrane fluidity of lipid layers of the intestinal brush border membranes and decreased the transepithelial electrical resistance (TEER) of Caco-2 cells. Therefore, these findings suggested that these sugar esters might improve the intestinal absorption of poorly absorbable drugs via a transcellular and a paracellular pathways.
    YAKUGAKU ZASSHI 01/2014; 134(1):47-53. DOI:10.1248/yakushi.13-00221-1
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    ABSTRACT: Arginine-rich peptides, including oligoarginines (Rn, n=7-12) are cell penetrating peptides (CPPs) and are useful for the intracellular delivery of membrane-impermeable substances. Endocytosed arginine-rich peptides can become trapped in endosomes, and the avoidance of endosomal retention is necessary for achieving effective cytosolic translocation. Our group has succeeded in enhancing the cellular uptake of oligoarginines by introducing short hydrophobic penetration accelerating sequences (Pas). The effectiveness of a Pas segment in improving the oligoarginine-mediated intracellular delivery of a biofunctional peptide was demonstrated through the efficient inhibition of glioma cell growth by a p53 C-terminal-derived retro-inverso peptide. The CPPs were expected to increase the penetration efficiency of low-permeability drugs through the intestinal epithelial cell layer into blood. Drugs conjugated to oligoarginines via a chemically stable linker tend to be retained in the negatively charged intracellular compartment due to the strongly cationic peptides. Our group has proposed the use of a self-cleavable linker strategy that effectively releases the drugs from the oligoarginine peptide. Chemical-triggered self-cleavage produces the parent drug via intramolecular imide formation under physiological conditions. The designed model drug-oligoarginine conjugates were converted with the half-life (t1/2) values of 9-100 min. Conjugates possessing a short t1/2 of 9-10 min improved the transport rate of the parent model drug in a Caco-2 monolayer permeation assay. The Pas attachment to the oligoarginine was also found to be effective in this permeation assay. The Pas attachment may provide a new platform for facilitating arginine-rich CPP-mediated cargo transport.
    YAKUGAKU ZASSHI 01/2014; 134(1):55-61. DOI:10.1248/yakushi.13-00221-2
  • YAKUGAKU ZASSHI 01/2014; 134(3):349-50. DOI:10.1248/yakushi.13-00235-F
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    ABSTRACT: Naturally occurring polyhydroxylated amines such as (+)-1-deoxynojirimycin, polyoxamic acid, anisomycin, (-)swainsonine, and alexine stereoisomers, which have interesting biological activities including glucosidase- and mannosidase-inhibitory activity, immunoregulatory activity, and antibacterial effects, were synthesized stereoselectively starting from (S)-pyroglutamic acid derivatives. α,β-Unsaturated lactams ((S)-5-hydroxymethyl-2-oxo-3-pyrroline derivatives), α,β-unsaturated δ-lactone ((S)-4-amino-2-penten-5-olide derivative), and E-olefin ((S,E)-methyl-4-amino-5-hydroxypent-2-enoate derivative) from (S)-pyroglutamic acid derivatives were dihydroxylated using OsO4 in the presence of N-methyl morpholine N-oxide (NMO) to afford various chiral building blocks with different configurations. The stereoselectivity of cis-dihydroxylation for α,β-unsaturated lactams and α,β-unsaturated δ-lactone was very high, while the stereoselectivity was low for E-olefin. Therefore, the double asymmetric induction of E-olefin using K2OsO4 with chiral ligands was successively applied to yield high stereoselectivity. (2R,3S)-2-Hydroxymethyl-3-hydroxypyrrolidine and Gaissman-Weiss lactone, important intermediates for the preparation of pyrrolizidine alkaloids, were synthesized from a (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidinone derivative derived from α,β-unsatulated lactam. (+)-1-Deoxynojirimycin was synthesized from a (2S,3R,4R)-methyl 4-amino-2,3,5-trihydroxypentanoate derivative of E-olefin. (-)-Swainsonine and its stereoisomers were synthesized from (2R,3S,4R)- or (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine derivatives of α,β-unsaturated δ-lactone or α,β-unsaturated lactam. The key reaction was diastereoselective allylation of the aldehyde derived from the corresponding 2-hydroxymethylpyrrolidine derivatives with various allylation reagents. The high diastereoselectivity could be explained by cyclic chelate formation between metals and the α-aminocarbonyl group or β-alkoxycarbonyl group, in which the nucleophile approaches from the less hindered face. Four alexine stereoisomers were synthesized from (2R,3R,4S,5R)- and (2R,3R,4S,5S)-2,3-dihydroxymethyl-3,4-dihydroxyl pyrrolidine derivatives of α,β-unsaturated lactam.
    YAKUGAKU ZASSHI 01/2014; 134(1):77-88. DOI:10.1248/yakushi.13-00217
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    ABSTRACT: Academic detailing, interactive information services by pharmacists for clinicians, has been getting interests in the US and European countries. A systematic review of randomized controlled trials supported the effectiveness of academic detailing. Knowledge of evidence-based medicine and clinical practice guidelines is one of the essential bases for pharmacists to promote these activities. In addition, pharmacists need to understand attitudes and ways of thinking of clinicians toward medicines. Through communications and information sharing between clinicians and pharmacists, collaborations to modify and improve the use of medicines should be facilitated. On these grounds, academic detailing will be able to play an important role in real healthcare circumstances.
    YAKUGAKU ZASSHI 01/2014; 134(3):367-70. DOI:10.1248/yakushi.13-00235-4
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    ABSTRACT: On dispensing powdered antineoplastic medicines, it is important to prevent cross-contamination and environmental exposure. Recently, we developed a method for blending powdered medicine in a disposable ointment container using a planetary centrifugal mixer. The disposable container prevents cross-contamination. In addition, environmental exposure associated with washing the apparatus does not arise because no blending blade is used. In this study, we aimed to confirm the uniformity of the mixture and weight loss of medicine in the blending procedure. We blended colored lactose powder with Leukerin(®) or Mablin(®) powders using the new method and the ordinary pestle and mortar method. Then, the blending state was monitored using image analysis. Blending variables, such as the blending ratio (1:9-9:1), container size (35-125 mL), and charging rate (20-50%) in the container were also investigated under the operational conditions of 500 rpm and 50 s. At a 20% charging rate in a 35 mL container, the blending precision of the mixtures was not influenced by the blending ratio, and was less than 6.08%, indicating homogeneity. With an increase in the charging rate, however, the blending precision decreased. The possible amount of both mixtures rose to about 17 g with a 20% charging rate in a 125 mL container. Furthermore, weight loss of medicines with this method was smaller than that with the pestle and mortar method, suggesting that this method is safer for pharmacists. In conclusion, we have established a precise and safe method for blending powdered medicines in pharmacies.
    YAKUGAKU ZASSHI 01/2014; 134(5):665-670. DOI:10.1248/yakushi.14-00018
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    ABSTRACT: An emerging aspect of redox signaling is the signaling pathway mediated by electrophilic byproducts, such as nitrated cyclic nucleotide (8-nitro-cGMP), generated via reactions of reactive oxygen species (ROS), NO, and their secondary products. We recently clarified that enzymatically-generated hydrosulfide derivatives regulate the metabolism and signaling of 8-nitro-cGMP. Although hydrogen sulfide was proposed to be a gaseous signaling mediator, its exact nature and physiological functions remain obscure. We thus found that particular hydropersulfide derivatives rather than hydrogen sulfide greatly ameliorated chronic heart failure after myocardial infarction in vivo in mice. This potent cardioprotective effect resulted from strong suppression of H-Ras signaling activated by electrophilic stimulation with 8-nitro-cGMP functioning as a second messenger for the redox signaling induced by NO and ROS. A significant amount of 8-nitro-cGMP was formed in the heart tissue after myocardial infarction, and hydrogen sulfide exogenously administered completely nullified this formation. We have reportedly shown that hydropersulfide effectively thiolated electrophiles in cells, which is best represented by 8-nitro-cGMP. Our current study indicates that electrophile thiolation may be a unique mechanism regulating ROS signaling and redox homeostasis, which may thus promote further development of prophylactic and therapeutic options for oxidative stress-related diseases.
    YAKUGAKU ZASSHI 01/2014; 134(4):515-9. DOI:10.1248/yakushi.13-00251-3
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    ABSTRACT: We tested a community electronic prescription system (K-CHOPS/PPISS) that we developed in Kagawa, Japan, which connects the prescribing physicians, pharmacists at community pharmacies, and patients through a community data center server. Physicians can send prescriptions, diagnoses, and laboratory data to the datacenter. Pharmacists in community pharmacies can access their patients' information through the datacenter and can return corrected prescriptions and reports containing guidance and adverse events to the hospital or clinic where the prescription was issued. Patients can then see their dispensed medications on their PCs, cellular phones, and smart phones. Additionally, patients can input medication-taking records, allergy and adverse drug reactions (ADR), any over-the-counter drug and supplements that they take, and their physical condition through the devices. The system enables pharmacists to appropriately advise and monitor ADR based on patient clinical data and enables physicians to accurately know the medications handed to patients and advisories issued by the pharmacists. Further, physicians and pharmacists can see the patients' condition which they entered on their devices if the patients agree. These would be helpful for avoiding ADR. The information accumulated in the data center can be potentially utilized for evaluation of the effectiveness and ADR of medications and for development of innovative medication. Discussion of the pros and cons for such utilization is needed.
    YAKUGAKU ZASSHI 01/2014; 134(5):589-593. DOI:10.1248/yakushi.13-00256-2
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    ABSTRACT: Since the Fukushima nuclear plant accident following the great East Japan earthquake on March 11, 2011, we have been warned to be careful about possible radiation exposure almost every day in newspapers and on TV. Radioactive iodine ((131)I) and cesium ((134)Cs, (137)Cs) produced by nuclear reactions were released into the air during and after the accident, and have been scattered by the winds in Tohoku and in the Kanto district. Even today, 2 years after the accident, there is great public concern about possible pollution of foodstuffs and fishery products with radioactive cesium, not only in Japan, but also in other countries. On the other hand, decontamination work has been proceeding, including removal of contaminated soil near the accident site. Since the accident, many media reports have continued to tell us only that current dose levels of radiation are not dangerous to human health. But, many people are not satisfied with such vague statements, and want to understand the situation in more detail. So, it is important to provide basic education about the effects of radiation to the general public. I am a professor of the Department of Radiation Biosciences at Tokyo University of Science, and so I am very familiar with radiation and its dangers. So, in my lecture today, we would like to explain the effects of radiation and put the present situation into perspective, so that people will better understand the risks, and not be unnecessarily afraid.
    YAKUGAKU ZASSHI 01/2014; 134(2):155-61. DOI:10.1248/yakushi.13-00227-4
  • YAKUGAKU ZASSHI 01/2014; 134(2):133. DOI:10.1248/yakushi.13-00227-F
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    ABSTRACT: Skin is the structure that covers our body and protects it from not only the entry of pathogens or allergens but also from the leakage of water, solutes or nutrients. These outside-in and inside-out skin barrier functions are dependent on the epidermis, a stratified epithelial cellular sheet. While mucus covers the epidermis in fish and amphibian tadpoles, terminally differentiated cornified cellular sheets called stratum corneum (SC) constitute the outermost epidermal barrier in amphibian adults, reptiles, birds and mammals. Beneath the mucus or SC, apical paracellular spaces of epidermal cells are sealed with tight junctions (TJs) that limit paracellular leakage of water and electrolytes to maintain fluid homeostasis. We applied time-of-flight secondary-ion-mass-spectrometry (TOF-SIMS) imaging technology to analyze the SC in skin sections, and found that the SC consisting of three layers of distinct functional properties. Under the barriers of the SC and TJ, antigen-presenting dendritic cells called Langerhans cells (LCs) distribute within the epidermis. LCs elongate their dendrites to penetrate through epidermal TJs upon activation and uptake antigens from extra-TJ environment. During antigen uptake, new TJs are formed between keratinocytes and LC dendrites to maintain the integrity of epidermal TJ barriers. To understand the epidermal barrier system and its deficiency observed in human skin diseases, we need to re-evaluate human epidermal barrier as a composite barrier consisting of SC and TJs and to investigate the molecular mechanism and immunological consequences of the extra-TJ antigen uptake activity of LCs.
    YAKUGAKU ZASSHI 01/2014; 134(5):623-627. DOI:10.1248/yakushi.14-00006-2
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    ABSTRACT: Using a taste sensor in the field of medical products has the following four main purposes: (1) Ensuring that investigational product and placebo are indistinguishable; (2) Formulation design; (3) Quality control; (4) Benchmark test. Unlike evaluating a taste of food, roughly predicting a taste of drug without human sensory test and quantitative evaluation using small quantity of drug sample are more important than evaluation of the nuances of homogeneous taste and preference. Here are some examples of using taste sensor for these purposes. (1) We predicted a taste of suspension of phosphatic drug substance in an early phase of development using a taste sensor. As a result, the suspension seemed to have sour and bitter taste. Then we made placebo solution of citric acid similar taste as much like active suspension to ensure indistinguishable taste from each other. (2) A taste of orally disintegrating tablet (ODT) in the mouth is important to drug adherence. The taste of an ODT was then evaluated in chronological order by combining the taste sensor with the new disintegration testing apparatus to design easy-to-take formulation. (3) We evaluated taste variation of a commercial product in batch-to-batch and identified the cause of the variation. (4) We did benchmark test for easy-to-take of commercial ODTs in vitro. There is great variability among these products in the disintegrating profile and the taste.
    YAKUGAKU ZASSHI 01/2014; 134(3):325-31. DOI:10.1248/yakushi.13-00234-4
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    ABSTRACT: Within an epithelial cellular sheet, the paracellular pathway can be divided into two routes: one between two adjacent cells and one at tricellular contacts, where the vertices of three cells meet. For epithelial barrier function, tight junctions restrict solute permeability through the paracellular pathway between two cells, while tricellular contacts contain specialized structures of tight junctions, named tricellular tight junctions (tTJs). Two types of membrane proteins, tricellulin and angulin family proteins (angulin-1/LSR, angulin-2/ILDR1 and angulin-3/ILDR2) have been identified as molecular components of tTJs. Angulins recruit triellulin to tTJs and these tTJ-associated proteins are required for normal tTJ formation as well as strong epithelial barrier function. Furthermore, mutations in tricellulin and angulin-2/ILDR1 genes cause autosomal recessive familial deafness, DFNB49 and DFNB42, respectively. Further analyses of the angulin-tricellulin system should lead to better understanding of the molecular mechanism and regulation of tTJs.
    YAKUGAKU ZASSHI 01/2014; 134(5):615-621. DOI:10.1248/yakushi.14-00006-1
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    ABSTRACT: Positron emission computed tomography (PET) imaging is a clinically translatable technology with the potential to accelerate drug research and development. Therapy monitoring by non-invasive PET imaging study allows a straightforward translation from preclinical to clinical research. In fact, PET imaging is making a major contribution to drug development today and will continue to grow in value. We hereby demonstrate that PET imaging capabilities and our experiences focused on oncology and central nervous system (CNS) therapeutic areas in drug research and development. PET with labeled anticancer drug may be an ideal biomarker for identification of treatment-responsive populations. Using non-invasive PET imaging with labeled anticancer drug, we investigated whether uptake of anticancer drug in tumors is associated with the efficacy. Brain concentration of CNS drug could be obtained according to the radioactivity of PET-labeled CNS drug in brain measured by PET. Usually, blood-brain barrier (BBB) penetration in non-human primates is a good indication for human BBB penetration and we have performed brain PET study in conscious rhesus macaques using special PET camera for non-human primate. Recently, we have successfully identified (18)F-fluorodeoxyglucose (FDG) PET is useful as a tool for the predictive imaging biomarker against CNS drug-induced neuronal degeneration/cell death and available in the clinical trial. Finally, we would like to mention that how imaging biomarkers should be applied to clinical trials including investigational trials beyond preclinical study.
    YAKUGAKU ZASSHI 01/2014; 134(4):465-72. DOI:10.1248/yakushi.13-00248-2
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    ABSTRACT: Central sensitization in the spinal cord is well known to be involved in chronic pain. Recent investigations indicated that the protein expressions involving the synaptic plasticity are changed in several brain areas under a chronic pain condition. These changes in supraspinal neural function might cause the emotional and memory dysfunction. It is also possible that these changes are involved in the chronic pain. Indeed, since the improvement of spinal and peripheral sensitization showed limited relief in the neuropathic pain, the sensitization of supraspinal nociceptive transmission might be involved in the expression of chronic pain. We recently found that intra-thalamic treatment with excitatory neurotransmitter glutamate caused hyperalgesia, which is mediated by the stimulation of glutamate N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Moreover, intracerebroventricular treatment with gabapentin, a calcium channel alpha2delta-1 subunit blocker, attenuated the hyperalgesia in the nerve-injury model of mice. These results suggest that the sensitization of supraspinal nociceptive transmission is involved in neuropathic pain. It is also indicated that neuropathic pain is resulted from the activations of spinal glial cells. Likewise, the supraspinal glial activation was observed in the neuropathic pain. Therefore, the sensitization of supraspinal nociceptive transmission might be important for a chronic pain. In this review, we would like to discuss the possible involvement of the supraspinal sensitization in neuropathic pain and in its application for the curative treatment in chronic pain.
    YAKUGAKU ZASSHI 01/2014; 134(3):387-95. DOI:10.1248/yakushi.13-00236-3
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    ABSTRACT: Learning chemistry is cumulative: basic knowledge and chemical calculation skills are required to gain understanding of higher content. However, we often suffer from students' lack of learning skills to acquire these concepts. One of the reasons is the lack of adequate training in the knowledge and skills of chemistry, and one of the reasons for this lack is the lack of adequate evaluation of training procedures and content. Team-based learning (TBL) is a strong method for providing training in the knowledge and skills of chemistry and reaffirms the knowledge and skills of students of various levels. In our faculty, TBL exercises are provided for first-year students concurrently with lectures in physical chemistry and analytical chemistry. In this study, we researched the adoption of a peer evaluation process for this participatory learning model. Questionnaires taken after TBL exercises in the previous year showed a positive response to TBL. Further, a questionnaire taken after TBL exercises in the spring semester of the current year also yielded a positive response not only to TBL but also to peer evaluation. In addition, a significant correlation was observed between the improvement of students' grades in chemistry classes and the feeling the percentage (20%) of peer evaluation in overall evaluation low (logistic regression analysis, p=0.022). On the basis of the findings, we argue that TBL provides a generic, practical learning environment including an effective focus on learning strategy and evaluation of knowledge, skills, and attitudes, and studies on the educational effects of TBL and peer evaluation.
    YAKUGAKU ZASSHI 01/2014; 134(2):185-94. DOI:10.1248/yakushi.13-00231-3
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    ABSTRACT: Since osteoporosis is a major public health problem in Japan, it is important to clarify the effect of high-mineral drinking water consumption on osteogenesis. Therefore, in this study, we investigated the relationship between high-mineral drinking water consumption and osteogenesis in ovariectomized rats that received a low-calcium diet and purified water (PW group) or a low-calcium diet and high-mineral drinking water (CR group). High-mineral drinking water affected the rats' body weight. After 3 months, the bone density of the CR group was higher than that of the PW group (p<0.05). Furthermore, the CR group showed a decrease in the amount of calcium in the bones after 3 months. These results suggest that high-mineral drinking water contributes to the maintenance of bone density and not to the amount of calcium in bone. On the other hand, serum alkaline phosphatase levels in the PW group at 3 months were higher than those in the CR group, which indicates that the blood concentration of calcium in the CR group was maintained. Moreover, the amount of magnesium in the bones and the blood concentration of magnesium in the CR group after 3 months were higher than the corresponding values in the PW group. These results suggest that consumption of high-mineral drinking water could be beneficial for osteogenesis (i.e., for maintaining bone quantity).
    YAKUGAKU ZASSHI 01/2014; 134(5):679-685. DOI:10.1248/yakushi.14-00014