All issues
Predecessor
Volume 134, Issue 4
Displaying 1-18 of 18 articles from this issue
- |<
- <
- 1
- >
- >|
Symposium Reviews
-
Hisaharu Yamada2014 Volume 134 Issue 4 Pages 457-458
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSDownload PDF (167K) -
Soonih Kim2014 Volume 134 Issue 4 Pages 459-463
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSA microdose clinical trial may be useful as a safe early-phase exploratory study using doses as low as 100 μg or less for determination of the disposition of a candidate compound in humans in a short period of time. This may increase confidence in candidate compounds, especially those for which it is difficult to predict disposition based on the results of in vitro or preclinical studies. In this study, we examined microdose trials performed in the preclinical stage for two first-in-class compounds with a new mechanism of action. These compounds showed species difference in first pass metabolism in the digestive tract and liver, causing uncertainty in prediction of disposition in humans. For this reason, first-in-human microdose clinical trials were performed. The results showed that the two compounds had effective blood concentrations after oral administration at a dose of 100 mg qd. Administration of an extremely small dose of one 14C-labeled compound permitted identification of major metabolites. No toxic metabolites were detected. The preclinical toxic dose was determined based on prediction of blood exposure at the estimated maximum clinical dose. For the other candidate compound, the findings of the microdose trial indicated a high bioavailability after oral administration and low hepatic clearance after intravenous administration. These results suggested only a small risk of a change in disposition in patients with hepatic disorder. The data obtained for the two compounds suggest that microdose clinical trials can be useful for improving the process of candidate selection in the preclinical stage.
View full abstractDownload PDF (257K) -
Sosuke Miyoshi2014 Volume 134 Issue 4 Pages 465-472
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSPositron 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 18F-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.
View full abstractDownload PDF (1593K) -
Nobuharu Goto, Masayuki Suzuki2014 Volume 134 Issue 4 Pages 473-483
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSThe premise of the implementation of eligible pharmacodynamic biomarkers (PD markers) in clinical development of drugs is based on their qualification and understanding of human disease networks on a molecular level, which may be relevant to risk factors, pathogenesis, prognosis, and relapse/remission. Especially, information on PD markers characterized with drug exposure in target tissues, drug binding to target molecules, and linkage to clinical endpoints in early drug development stage can be critical for GO/NO GO decision for the next late clinical stages. Moreover, early confirmation of reliable biomarker method validations consisting of analytical performance and sample handling performance classified with fit-for-purpose strategy would be more crucial in practice for trouble-free biomarker implementation. For clinical setting of PD markers and final success of drug regulatory approval, good interpersonal communications among various members such as medical-, biological-, pharmacological-, toxicological-, pharmacokinetics-, statistical-scientists, and bioanalysts are also required. We are now trying to establish a knowledge-based biomarker selection method using commercially available databases, and our policy of fit-for-purpose-based biomarker method validation. In this article, we will report our current thinking and case-studies mentioned above.
View full abstractDownload PDF (690K) -
Shyh-Yuh Liou2014 Volume 134 Issue 4 Pages 485-490
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSThe Human Genome Project was completed in 2003. A catalog of common genetic variants in humans was built at the International HapMap Project. These variants, known as single nucleotide polymorphisms (SNPs), occur in human DNA and distributed among populations in different parts of the world. By using the Linkage Disequilibrium and mapping blocks are able to define quantitative characters of inherited diseases. Currently 50 K-5.0 M microarray are available commercially, which based on the results of following the ENCODE & 1000 genome projects. Therefore the genome wide association study (GWAS) has become a key tool for discovering variants that contribute to human diseases and provide maximum coverage of the genome, in contrast to the traditional approach in which only a few candidates genes was targeted. The available public GWAS databases provided valuable biological insights and new discovery for many common diseases, due to the availability of low cost microarray. The GWAS has the potential to provide a solution for the lack of new drug targets and reducing drug failure due to adverse drug reactions either. These are critical issues for pharmaceutical companies. Here, the Japan PGx Data Science Consortium (JPDSC), which was established on February 20, 2009 by six leading pharmaceutical companies in Japan, was introduced. We believe that the efforts of stakeholders including the regulatory authorities, health providers, and pharmaceutical companies to understand the potential and ethical risk of using genetic information including GWAS will bring benefits to patients in the future.
View full abstractDownload PDF (324K) -
Yoshiaki Tazawa2014 Volume 134 Issue 4 Pages 491-498
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSRecently companion diagnostics (CoDx) have been getting more importance to promote personalized medicine which can improve not only the efficacy and safety of treatments but also increase the cost-effectiveness of medication. In July 2011, the U.S. Food and Drug Administration (FDA) notified the draft guidance for development of CoDx that recommends co-development of CoDx and a new drug as the best practice. The Ministry of Health, Labour and Welfare in Japan also issued on July 1, 2013, their official notification regarding considerable items on co-development of CoDx if the drug needs its dedicate diagnostics test or medical device to predict the efficacy or adverse reaction to the drug. However, since many useful and predictive biomarkers may be discovered after commercial launch of the drug, the validātion process and regulatory criteria of CoDx including Laboratory Developed Test (LDT) should be changed in order to avoid biomarker test lag. The reimbursement system, moreover, is not always suitable to assess the clinical and technological values of CoDx and those systems need to be reformed for encouraging personalized medicine with co-developed CoDx.
View full abstractDownload PDF (517K) -
Shigeki Sasaki, Shiro Futaki2014 Volume 134 Issue 4 Pages 499-500
Published: 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSDownload PDF (170K) -
Yoshiaki Yano, Kenichi Kawano, Kaoru Omae, Yuki Takeda, Sayaka Matsuza ...2014 Volume 134 Issue 4 Pages 501-506
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSGenetic fusion of fluorescent/luminescent proteins to a target protein for specific labeling in living cells has been widely used to investigate the intracellular trafficking and oligomerization of the proteins. However, several limitations of fluorescent/luminescent proteins, such as considerable size, difficulty in controlling labeling ratio in multicolor labeling, can obscure true behaviors of the target proteins. To overcome these difficulties, post-translational labeling methods using pairs of small genetically-encodable ‘tags’ and synthetic ‘probes’ targeting the tags have been widely studied in recent years. We have developed a quick tag-probe labeling method using a high-affinity heterodimeric coiled-coil formation between the E3 tag (EIAALEK)3 attached to the target protein and the K4 probe (KIAALKE)4 labeled with a fluorophore. The labeling is cell-surface-specific and completed within 1 min, therefore suitable for monitoring oligomerization/internalization of membrane proteins on living cell surface. Taking advantage of easiness in multicolor labeling, we show that the oligomeric state of membrane proteins can be precisely analyzed based on fluorescence resonance energy transfer. By using this method, we found that β2 adrenergic receptors do not form constitutive homooligomers, and homooligomerization is not necessary for the receptor function. Furthermore, the degree of internalization of the β2 receptors following agonist stimulation was evaluated by ratiometric detection of pH decrease in endosomes.
View full abstractDownload PDF (493K) -
Tatsuo Kurihara, Jun Kawamoto2014 Volume 134 Issue 4 Pages 507-513
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSPolyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) occur in biological membranes as acyl groups of phospholipids and exhibit remarkable physiological activities. In human, they have various beneficial effects on health such as protective effects against cardiovascular disease, inflammation, and cancer. We have been studying their physiological functions in bacteria, which have a much simpler membrane structure than eukaryotes. We found that the cell division of a marine bacterium, Shewanella livingstonensis Ac10, is inhibited and shows growth retardation by disruption of its EPA biosynthesis genes. We synthesized a fluorescent analog of EPA-containing phospholipids (EPA-PLs) as a chemical probe to analyze their subcellular distribution and found that it is localized at the center of the cell undergoing cell division. This localization was shown to depend on the structure of the hydrocarbon chain of the phospholipids. We also examined the effects of EPA-PLs on the folding of Omp74, a major membrane protein of this bacterium, by using liposomes and found that EPA-PLs facilitated the folding process. The results imply that EPA-PLs function as a chemical chaperone in the folding of membrane proteins. These findings would contribute to understanding of the physiological function of phospholipids with polyunsaturated fatty acyl chains in various biological membranes.
View full abstractDownload PDF (420K) -
Takaaki Akaike2014 Volume 134 Issue 4 Pages 515-519
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSAn 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.
View full abstractDownload PDF (406K) -
Yasushi Ishihama, Koshi Imami2014 Volume 134 Issue 4 Pages 521-527
Published: 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSReversible phosphorylation of proteins controlled by kinases and phosphatases is one of the most ubiquitous post-translational modifications, and regulates a variety of cell functions through cellular signal transduction pathways. These signals are involved in various diseases such as cancer and rheumatism, and often cause the disease itself or drive the progression. Quantitative phosphoproteomics based on liquid chromatography-tandem mass spectrometry combined with phosphopeptide enrichment and stable isotope labeling allows profiling thousands of phosphorylation sites on human proteins and has been applied to monitoring cellular phosphorylation dynamics induced by various growth factors, hormones and other perturbations including kinase inhibitors. Here, we employed these technologies to quantify the temporal response of phosphorylation dynamics in SKBR3 breast cancer cells to lapatinib, a kinase inhibitor for epidermal growth factor receptor (EGFR) and EGFR2 (also known as HER2). Among 4953 identified phosphopeptides from 1548 proteins, a small proportion (5-7%) was regulated at least twofold by 1-10 μM lapatinib. The results provide new insights into EGFR/HER2 regulation through region-specific phosphorylation, as well as a global view of the cellular signaling networks associated with the anti-breast cancer action of lapatinib.
View full abstractDownload PDF (499K) -
Hideyuki Yamada, Tomoki Takeda, Takayuki Koga, Yuji Ishii2014 Volume 134 Issue 4 Pages 529-535
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSThe sexual differentiation of animal fetuses and infants needs stimuli by sex steroids, which are produced in their own gonads, during a short window (‘critical period’) of pre- and post-natal periods. Our laboratory has conducted a series of studies focusing on the damage to next generations by dioxins. When pregnant rats are exposed to a prototype of dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 1 μg/kg), sexual immaturity such as defects in copulation behavior as well as growth retardation emerges in their pups. We have provided evidence that such disorders are evoked, if not all, from a transient reduction in the gonadal synthesis of sex steroids in fetuses/infants during the critical period. Our studies also revealed that TCDD initially reduces the pituitary expression of luteinizing hormone (LH) to exert the effect on steroidogenesis. Several mechanisms seem to be involved in a TCDD-induced reduction in LH expression. For example, a change in epigenetic regulation in the pituitary and impaired energy production in the hypothalamus are suggested to contribute to the above reduction. Current our study has demonstrated that a transient reduction in the pituitary-gonad axis fixes the lowered expression of hypothalamic gonadotropin-releasing hormone, resulting in defects in sexual behavior. Through these topics, we discuss the role of the critical period in differentiation and development.
View full abstractDownload PDF (519K)
Review
-
Yasuyuki Nomura2014 Volume 134 Issue 4 Pages 537-543
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSThe endoplasmic reticulum (ER) has physiological roles in the quality control of proteins. Various stresses (e.g., oxidation, aging) to the ER cause accumulation of unfolded/misfolded proteins in the ER lumen, followed by unfolded protein responses (UPR) such as refolding of unfolded protein by chaperons, ER-associated degradation (ERAD), and termination of protein synthesis. In this study, we identified protein-disulfide isomerase (PDI) upregulation by hypoxic stress in the ER of rat brains/astroglial cells. PDI overexpression attenuates hypoxia-induced neuronal apoptosis. In the brain autopsy of patients with sporadic Alzheimer's and Parkinson diseases, PDI was found to be S-nitrosylated, which reduced chaperone activity of PDI, suggesting the involvement of PDI in these diseases. In addition, we identified the novel E3 ubiquitin ligase HRD1 and observed that HRD1 activates degradation of Parkin-associated endothelin receptor-like receptor (Pael-R). HRD1 suppresses ER stress and Pael-R-induced apoptosis. Furthermore, HRD1 ubiquitinates amyloid precursor protein (APP), resulting in the decrease in amyloid β (Aβ) generation. Suppression of HRD1 expression causes APP accumulation and Aβ generation. HRD1 protein significantly decreased in the cerebral cortex of patients with Alzheimer's disease. HRD1 decrease in the brain of patients with Alzheimer's disease could be due to the insolubilization of HRD1 by oxidative stress. Subsequently, we observed that 4-phenylbutyric acid (4-PBA) possesses chaperone activity, which prevents protein aggregation and that 4-(4-methoxyphenyl)butanoic acid, a 4-PBA derivative, increases protective ability against ER stress-induced neuronal death. We believe that 4-PBA and its derivatives are potential candidates for pharmacological intervention for ER stress-induced neurodegenerative diseases.
View full abstractDownload PDF (566K)
Regular Articles
-
Yuji Suzuki, Haruko Yokoyama, Shinji Soeda, Kentaro Tokuoka, Masayuki ...2014 Volume 134 Issue 4 Pages 545-553
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
Advance online publication: January 18, 2014JOURNAL FREE ACCESSLow-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 non-steroidal anti-inflammatory drugs (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.
View full abstractDownload PDF (324K) -
Yuki Nakamura, Takanori Nakajima, Masanori Iwata, Yoshihiro Hayashi, K ...2014 Volume 134 Issue 4 Pages 555-561
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSRasilez® tablets (RTs) contain the active ingredient aliskiren, which is a direct renin inhibitor of the renin-angiotensin system and used for the treatment of hypertension. We examined the influence of temperature and humidity on the physico-pharmaceutical characteristics (mass, volume, hardness, elution) of RTs. The RTs were preserved under conditions in which the temperature and humidity were altered using the second-order spherical composite experimental design for multi-objective problems. The characteristics of RTs were influenced more by the humidity than temperature, and differed markedly with over 55% relative humidity (RH). The mass and volume were increased with increasing humidity, and the tablets swelled. The hardness after vacuum-drying of the tablets, which preserved moisture conditions, was increased. Semitransparent particles were observed in the cross-section of the drying tablets in which aliskiren crystal forms were changed to amorphous forms. The mean dissolution time (MDT) of tablets was reduced with increasing humidity. The critical relative humidity (CRH) of the tablets was 36.1%RH at 30°C. These results suggest that RTs, on moisture absorption, showed changes in not their appearance and hardness, but also in crystal forms and the elution characteristics of aliskiren.
View full abstractDownload PDF (791K)
Notes
-
Hiroki Satoh, Akiko Miki, Kazutoshi Maejima, Keiko Iizuka, Shoichi Yam ...2014 Volume 134 Issue 4 Pages 563-574
Published: 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSWe conducted a workshop that aimed to address the problems of collaboration between community and hospital pharmacists to provide safe outpatient chemotherapy and promote continuous collaboration. Thirty-nine pharmacists in Gunma were enrolled in the workshop and divided into five groups. Each group comprised similar number of community and hospital pharmacists in the neighboring area. Participants in these groups discussed using the KJ method and identified the following important and urgent problems; “lack of collaboration between hospitals and pharmacies” and “lack of exchanging patients’ information, including regimen”. To improve collaboration, the participants recommended a workshop or a study group and setting up a hotline, and to exchange patients’ information, they proposed to utilize a medicine notebook and reconfirm how to use these notebook. Furthermore, usage of cloud storage as a means to exchange patients’ information was discussed. Post-workshop questionnaire revealed that 97% participants acknowledged an increased awareness toward collaboration, and 90% participants were motivated to take more aggressive action for promoting collaboration; whereas, only 53% participants believed that they could summarize the problems and corrective measures in promoting collaboration. The workshop seemed to be productive in identifying the problems of collaboration and improving the awareness and motivation toward collaboration. However, it served only as a “trigger”, and therefore it is important for valuable “results” to continuously collaborate face-to-face between community and hospital pharmacists.
View full abstractDownload PDF (2286K) -
Midori Soda, Kaori Ogawa, Yaeko Harada, Suzuko Kawamoto, Miyoko Tanaka ...2014 Volume 134 Issue 4 Pages 575-580
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSHormone replacement therapy (HRT) given by injection or administered orally or topically can improve the QOL of patients with menopausal symptoms. Because patient comfort is influenced largely by the dosage form, pharmacists should understand the properties of each dosage form and provide appropriate information to individual patients. In this study, we investigated the understanding of medicines and diseases of patients receiving HRT and discuss the approaches pharmacists can take to improve patients' adherence. Thirty-seven patients (mean age 51.7±3.6 years) taking estradiol gel (Divigel® 1 mg) completed a questionnaire asked by their pharmacist. Responses indicated 70% of patients failed to use the gel as prescribed, and they had poor knowledge of both the sites where the gel shouldn't be applied and appropriate measures to take if having forgotten to apply the gel (43% and 11% correct understanding, respectively). Since the duration of HRT treatment for menopausal symptom is 2-5 years, patients should be administered the minimum effective dose in the shortest amount of time. Hence it is important to maintain patients' adherence particularly in this limited administration period. HRT guidelines define HRT outcome as not only improvement of menopausal symptoms but also suppression of bone resorption, improvement of glucose and lipid metabolism, and reduced prevalence of Alzheimer's disease. Accordingly, pharmacists should facilitate proper adherence to HRT to improve and maintain women's QOL in the perimenopausal period, necessitating they actively provide pharmaceutical care such as preparing useful instructions patients can repeatedly use and periodically checking patients' understanding of their HRT medications.
View full abstractDownload PDF (589K)
Errata
-
Kenji Sugibayashi, Hiroaki Todo, Wesam R. Kadhum2014 Volume 134 Issue 4 Pages 581
Published: April 01, 2014
Released on J-STAGE: April 01, 2014
JOURNAL FREE ACCESSDownload PDF (30K)
- |<
- <
- 1
- >
- >|