YAKUGAKU ZASSHI
 Abstracts 
Vol.130, No. 2 (2010)

--Foreword--

Cutting-edge Research on Hepatitis C Treatment and the Clinical Perspectives

Kiyohito YAGI^*,a and Toshimitsu HAYASHI^b

^aGraduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan, and ^bGraduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

--Reviews--

Antiviral Therapy for Chronic Hepatitis C: Current Status and Perspectives

Tetsuo TAKEHARA

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan

Antiviral therapy for chronic hepatitis C has advanced dramatically since the discovery of the hepatitis C virus and the introduction of interferon in early 1990s. An initial treatment regimen, 24 weeks of interferon monotherapy, achieved sustained virologic response, which is formally defined at 24 weeks after completion of the treatment, only for 5% of patients with genotype 1 high-viral load belonging to a difficult-to-treat group. Current standard therapy is a combination of pegylated interferon and ribavirin. Forty eight weeks of the combination therapy achieves successful viral eradication for 40-50% of genotype 1 patients while 24 weeks of that do so for 80% of genotype 2 patients. Early viral kinetics after the initiation of therapy is a useful predictor of the sustained virologic response for genotype 1 patients, serving as recommendation criteria for extended duration, 72 weeks, of combination therapy. New types of anti-HCV agents such as HCV protease and polymerase inhibitors are needed for patients that do not respond to combination therapy. Hepatitis C is not just an infectious disease, but a potentially serious liver disease progressing to end-stage liver cirrhosis and hepatocellular carcinoma. Antiviral therapy should be considered from the view point of suppressing liver-related death in hepatitis C virus-infected patients.

Key words--chronic hepatitis C; peginterferon; ribavirin; protease inhibitor

--Reviews--

Suppression of Hepatitis C Virus (HCV) Replication with Serine Palmitoyltransferase Inhibitor

Yuichi HIRATA,^a Masayuki SUDOH,^b and Michinori KOHARA^*,a

^aDepartment of Microbiology and Cell biology, The Tokyo metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan, and ^bKamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan

Hepatitis C virus (HCV) persists chronically in most infected patients, eventually causing chronic hepatitis, liver cirrhosis, and in some cases hepatocellular carcinoma. The combination therapy of PEG-IFN and ribavirin improves efficacy in many patients, although it does not lead to sufficient achievements in genotype 1b patients. To aid in invention of new anti-HCV reagents, we focused on host factors that contributed to HCV lifecycle. We identified serine palmitoyltransferase inhibitor as an anti-HCV reagent through high-throughput screening using HCV replicon cells. We investigated the mechanism of anti-HCV effect of SPT inhibitor. It has been reported that sphingolipids and cholesterol compose the lipid raft where replication of HCV occurs. We investigated the influence of SPT inhibitor to lipid rafts by analyzing the detergent-resistant membrane (DRM). The analysis showed that SPT inhibitor moved HCV RNA-dependent RNA polymerase (NS5B) to detergent-soluble fraction from DRM, and Biacore analysis indicated binding of sphingomyelin to NS5B. These results suggest that SPT inhibitor disrupts the interaction between NS5B and sphingomyelin. Moreover, we evaluated the anti-HCV effect of SPT inhibitor in vivo with humanized chimeric mice. SPT inhibitor led to rapid decline in serum HCV-RNA of about 1-2 log within 8 days. Furthermore, combination therapy of SPT inhibitor and PEG-IFN achieved about 3 log reduction in serum HCV-RNA.

Key words--hepatitis C virus (HCV); host factor; sphingomyelin; lipid raft

--Reviews--

Viral Safety of Biologicals: Evaluation of Hepatitis C Virus (HCV) Nucleic Acid Amplification Test (NAT) Assay and Development of Concentration Method of HCV for Sensitive Detection by NAT

Eriko UCHIDA^*,a and Teruhide YAMAGUCHI^b

^aDivision of Cellular and Gene Therapy Products, and ^bDivision of Biological Chemistry and Biologicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

The most important issue for the safety of biological products and blood products derived from human sources is how to prevent transmission of infectious agents. The hepatitis C virus (HCV) is a major public health problem due to its high prevalence. HCV is mainly transmitted by exposure to blood and highly infectious during the early window period with extremely low viral loads. Therefore it is important to develop more sensitive detection methods for HCV. In the case of blood products, both serological test and nucleic acid amplification test (NAT) are required to detect HCV. Since NAT is highly sensitive, establishment of a new standard is required for validation of NAT assay. NAT guideline and establishment of the standard for HCV RNA and HCV genotype panel is introduced in this review. On the other hand, to enhance the sensitivity of virus detection by NAT, a novel viral concentration method using polyethyleneimine (PEI)-conjugated magnetic beads (PEI beads) was developed. PEI beads concentration method is applicable to a wide range of viruses including HCV. Studies using the national standard for HCV RNA, HCV genotype panel and seroconversion panel, suggest that virus concentration method using PEI-beads is useful for improvement of the sensitivity of HCV detection by NAT and applicable to donor screening for HCV.

Key words--hepatitis C virus (HCV); viral safety; nucleic acid amplification test (NAT); standard; polyethyleneimine (PEI); virus concentration

--Reviews--

Evaluation and Application of Natural Products for Viral Infections

Kyoko HAYASHI,^* Toshimitsu HAYASHI, and Jung-Bum LEE

Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

The limited efficacy and significant clinical toxicity of combination interferone and ribavirin therapy have generated strong interest in developing novel inhibitors of hepatitis C virus (HCV) replication. Recently, a growing understanding of the structure and function of critical viral enzymes and the development of HCV replicons have accelerated the development of highly specific candidate antiviral agents. In the life cycle of HCV, enveloped virions bind and penetrate into host cell using viral envelope glycoproteins. In the cytoplasm, the viral RNA genome serves as mRNA, and produces viral protein as a long polyprotein that is cleaved by both host and viral proteases. Progeny virions assemble by budding into ER/Golgi apparatus, where the glycoproteins maturate, and are released at the cell surface. All stages of replication cycle from the attachment of virus to the release of progeny should be antiviral targets. We have searched for antiviral candidates from natural resources for about 20 years. So far, we have found several classes of compounds with unique antiviral action. Among them, anionic substances interfere with virus attachment and/or entry, several substances inhibit the maturation of virus-specific glycoproteins, low molecules can inhibit the virus release from infected cells, glycerol derivatives reduce the pathogenicity of virus, and some compounds exert virucidal action that impairs the ability of virus to infect host cells. These substances might be worthy to be evaluated as novel anti-HCV agents by using HCV replication systems in cultured cell lines.

Key words--natural product; hepatitis C virus; antiviral target; drug resistance

--Foreword--

Frontier of Ion Pump Research

Magotoshi MORII^*,a and Hideki SAKAI^b

^aFaculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki-cho, Suzuka, Mie 513-8670, Japan, and ^bGraduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

--Reviews--

Mechanism of Ca²⁺ Pump as Revealed by Mutations, Development of Stable Analogs of Phosphorylated Intermediates, and Their Structural Analyses

Hiroshi SUZUKI,^* Kazuo YAMASAKI, Takashi DAIHO, and Stefania DANKO

Department of Biochemistry, Asahikawa Medical College, 2-1-1-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan

Sarco(endo)plasmic reticulum Ca²⁺-ATPase is a representative member of P-type cation transporting ATPases and catalyzes Ca²⁺ transport coupled with ATP hydrolysis. The ATPase possesses three cytoplasmic domains (N, P, and A) and ten transmembrane helices (M1-M10). Ca²⁺ binding at the transport sites in the transmembrane domain activates the ATPase and then the catalytic aspartate is auto-phosphorylated to form the phosphorylated intermediate (EP). Structural and functional studies have shown that, during the isomerization of EP in the Ca²⁺ transport cycle, large motions of the three cytoplasmic domains take place, which then rearranges the transmembrane helices thereby destroying the Ca²⁺ binding sites, opening the lumenal gate, and thus releasing the Ca²⁺ into lumen. Stable structural analogues for the Ca²⁺-occluded and -released states of phosphorylated intermediates and for the transition and product states of the phosphorylation and dephosphorylation reactions were developed for biochemical and atomic-level structural studies to reveal the coupled changes in the catalytic and transport sites. Mutation studies identified the residues and structural regions essential for the structural changes and Ca²⁺ transport function. Genetic dysfunction of Ca²⁺-ATPase causes various isoform-specific diseases. In this manuscript, recent understanding of the Ca-ATPase will be reviewed.

Key words--sarco(endo)plasmic reticulum ATPase (SERCA); Ca²⁺-ATPase; Ca²⁺-pump; P-type ATPase

--Reviews--

H⁺-transporting ATP Synthases: Insights into How Their Electrochemically Driven Motor Might Serve as a Drug Target

Masatomo MAEDA

Department of Molecular Biology, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Shiwa, Iwate 028-3694, Japan

ATP synthases, widely distributed in bacteria, eukaryotic mitochondria and chloroplasts, are highly conserved multi-subunit complexes. Although the conserved acidic residue in the transmembrane helix of the c subunit functions in proton transport, the surrounding residues differ among species. Such divergence could lead to different regulatory modes since pH-dependent proton transport has been demonstrated in Escherichia coli with a c subunit carrying an additional acidic residue in the helix. There is further divergence in the number of c subunits that form the ring structure in F₀. Recently, it was also suggested that certain chemicals recognize the a and c subunits of pathogenic bacterial F₀. Since there may be structural divergence even in well-conserved ATP synthases, the c subunit-ring as well as the a subunit in F₀ could be targets for drugs for specific bacterial species.

Key words--ATP synthase; F₀F₁; proton transport; c subunit; a subunit; antibacterial drug

--Reviews--

Structural and Functional Properties of the C-terminal Region of Mitochondrial ADP/ATP Carrier

Yasuo SHINOHARA,^*,a,b Mitsuru HASHIMOTO,^c Yoshitaka KIHIRA,^d Kazuto OHKURA,^e Eiji MAJIMA,^f and Hiroshi TERADA^g

^aInstitute for Genome Research, ^dInstitute of Health Biosciences, University of Tokushima, Kuramotocho-3, Tokushima 770-8503, Japan, ^bFaculty of pharmaceutical Science, University of Tokushima, Shomachi-1, Tokushima 770-8505, Japan, ^cFaculty of pharmaceutical Science, Matsuyama University, Bunkyocho-4, Matsuyama 790-8578, Japan, ^eFaculty of Pharmacy, Chiba Institute of Science, Shiomicho-3, Choshi 288-0025, Japan, ^fProtenova, Inc., Hayashicho 2217, Takamatsu 761-0301, Japan, and ^gFaculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda 278-8510, Japan

Mitochondrial ADP/ATP carrier (AAC) is a protein catalyzing the transport of adenine nucleotides across inner mitochondrial membrane. In this review article, we first briefly introduce structural and functional properties of this protein. Next, we describe the results of our recent studies on the difference in the C-terminal region between yeast type 2 AAC isoform and bovine type 1 AAC isoform. Furthermore, based on the reactivities of cysteine residues that replaced amino acids in the sixth transmembrane segment, the probable structural features of the C-terminal region of this carrier are discussed.

Key words--ADP/ATP carrier (AAC); solute carrier family; mitochondria; transport mechanism; yeast

--Reviews--

A Novel Ratchet Mechanism of Gastric H⁺,K⁺-ATPase Revealed by Electron Crystallography of Two-dimensional Crystals

Kazuhiro ABE,^* Kazutoshi TANI, Tomohiro NISHIZAWA, and Yoshinori FUJIYOSHI

Department of Biophysics, Faculty of Science, Kyoto University, Oiwake, Kitashirakawa, Sakyo-ku, Kyoto 606-0852, Japan

Acid secretion by the stomach results in a pH of about 1. This highly acidic environment is essential for digestion and also acts as a first barrier against bacterial and viral infections. Conversely, too much acid secretion causes gastric ulcer. The mechanism by which this massive proton gradient is generated is of considerable biomedical interest. In this review, we introduce the first molecular model for this remarkable biological phenomenon. The structure of H⁺,K⁺-ATPase at 6.5 - resolution was determined by electron crystallography of two-dimensional crystals. The structure shows the catalytic α-subunit and the non-catalytic β-subunit in a pseudo-E₂P conformation. Different from Na⁺,K⁺-ATPase, the N-terminal tail of the β-subunit is in direct contact with the phosphorylation domain of the α-subunit. This interaction may hold the phosphorylation domain in place, thus stabilizing the enzyme conformation and preventing the reverse reaction of the transport cycle. Indeed, truncation of the β-subunit N-terminus allowed the reverse reaction to occur. These results suggest that the N-terminal tail of the β-subunit functions as a “ratchet”, preventing inefficient transport and reverse-flow of protons. We can thus provide a mechanistic explanation for how the H⁺,K⁺-ATPase can generate a million-fold proton gradient across the gastric parietal cell membrane, the highest cation gradient known in any mammalian tissue.

Key words--gastric proton pump; H⁺,K⁺-ATPase; cryo-electron microscopy; two-dimensional crystal; membrane protein structure; P-type ATPase

--Reviews--

Molecular Mechanisms Underlying PGF2α-induced Hypertrophy of Vascular Smooth Muscle Cells

Chunyuan FAN,^*,a Masato KATSUYAMA,^b Haiyan WEI,^c Qingjie XIA,^a Wentao LIU,^a and Chihiro YABE-NISHIMURA^b

^aDepartment of Nephrology, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, 1# Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu, 610041, China, ^bDepartment of Pharmacology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan, and ^cState Key Laboratory of Biotherapy, West China Hospital and School of Life Science, Sichuan University, 1# Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu, 610041, China

The present review focuses primarily on the studies we made in recent years to improve the understanding of the molecular mechanisms of PGF2α-induced hypertrophy of Vascular Smooth Muscle Cells (VSMC). In this review, we will summarize the recent findings in the context of the PGF2α signaling pathway in three parts: PGF2α binding to its receptor, transactivation of EGF receptor, two independent signaling transduction pathways increasing the expression of NOX1 gene.

Key words--PGF2α; NOX1; hypertrophy; Vascular Smooth Muscle Cells (VSMC)

--Regular Articles--

Studies on Effect of Stress Preconditioning in Restrain Stress-induced Behavioral Alterations

Rajneet KAUR, Amteshwar Singh JAGGI, and Nirmal SINGH^*

Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India

Stress preconditioning has been documented to confer on gastroprotective effects on stress-induced gastric ulcerations. However, the effects of prior exposure of stress preconditioning episodes on stress-induced behavioral changes have not been explored yet. Therefore the present study was designed to investigate the ameliorative effects of stress preconditioning in immobilization stress-induced behavioral alterations in rats. The rats were subjected to restrain stress by placing in restrainer (5.5 cm in diameter and 18 cm in length) for 3.5 h. Stress preconditioning was induced by subjecting the rats to two cycles of restraint and restrain-free periods of 15 min each. Furthermore, a similar type of stress preconditioning was induced using different time cycles of 30 and 45 min. The extent and severity of the stress-induced behavioral alterations were assessed using different behavioral tests such as hole-board test, social interaction test, open field test, and actophotometer. Restrain stress resulted in decrease in locomotor activity, frequency of head dips and rearing in hole board, line crossing and rearing in open field, and decreased following and increased avoidance in social interaction test. Stress preconditioning with two cycles of 15, 30 or 45 min respectively, did not attenuate stress-induced behavioral changes to any extent. It may be concluded that stress preconditioning does not seem to confer any protective effect in modulating restrain stress-induced behavioral alterations.

Key words--restrain stress; stress preconditioning; behavior; social interaction

--Regular Articles--

Determination of Organotin Compounds in Water Soluble Paints and Adhesives by GC-MS

Tsuyoshi KAWAKAMI,^*,a Kazuo ISAMA,^a Harunobu NAKASHIMA,^b Tomoko OOSHIMA,^c Toshie TSUCHIYA,^a and Atsuko MATSUOKA^a

^aDivision of Medical Devices, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan, ^bOsaka Prefectural Institute of Public Health, 3-69 Nakamichi 1-chome Higashinari-ku, Osaka 537-0025, Japan, and ^cOsaka City Institute of Public Health and Environmental Sciences, 8-34 Tojocho, Tennoji-ku, Osaka 543-0026, Japan

The use of tributyltin (TBT) and triphenyltin (TPT) in some household products are prohibited by “Act on the Control of Household Products Containing Harmful Substances” in Japan. In this study, methods for determination of TBT and TPT in water soluble paints and adhesives were developed by GC-MS. These compounds in paints and adhesives, which were mainly composed of vinyl acetate, urethane and acryl resins, and chloroprene rubber, were firstly extracted with HCl-acetone, and then extracted with hexane. On the other hand, the adhesive composed of natural rubber was firstly dispersed in water before acidification. The organotins were extracted with hexane from this solution and then these compounds were extracted with acetonitrile from hexane extract. These extracts were purified by a florisil cartridge column after ethyl-derivation with sodium tetraethylborate, and analyzed by GC-MS. The quantifications using deuterated compound of both organotins as surrogate standard were conducted, and good results were obtained. The recoveries were 81 to 118% and the coefficients of variation were 0.83 to 4.3% (TBT and TPT added; 5 μg/g). The method quantification limits were 0.0090 to 0.025 μg/g, which were lower than those of an official method. These methods were applied to monobutyltin (MBT), dibutyltin (DBT), monophenyltin (MPT), and diphenyltin (DPT). DBT and DPT in paints and adhesives were quantified, except for DPT in natural rubber. These methods were applied to commercial products. DBT was detected at low concentrations (t.r.-0.19 μg/g) in some paint samples, while TBT and TPT were not detected in all samples.

Key words--tributyltin; triphenyltin; GC-MS; water soluble paint; water soluble adhesive; ethyl-derivation

--Regular Articles--

Characteristics of Cannabis sativa L.: Seed Morphology, Germination and Growth Characteristics, and Distinction from Hibiscus cannabinus L.

Kayo YOSHIMATSU,^* Takashi KITAZAWA, Noriaki KAWANO, Osamu IIDA, and Nobuo KAWAHARA

Research Center for Medicinal Plant Resources, National Institute of Biomedical Innovation, 1-2 Hachimandai, Tsukuba, Ibaraki 305-0843, Japan

Illegal cannabis (Cannabis sativa L.) cultivation is still a social problem worldwide. Fifty inquiries on cannabis that Research Center for Medicinal Plant Resources (Tsukuba Division) received between January 1, 2000 and March 31, 2009 were itemized in to 8 categories; 1: seed identification, 2: plant identification, 3: indoor cultivation, 4: outdoor cultivation, 5: germination and growth characteristics, 6: expected amount of cannabis products derived from illegal cannabis plant, 7: non-narcotic cannabis and 8: usage of medicinal cannabis. Top three inquiries were 1: seed identification (16 cases), 3: indoor cultivation (10 cases) and 4: outdoor cultivation (6 cases). Characteristics of cannabis, namely seed morphology, germination and growth characteristics, and distinction from kenaf (Hibiscus cannabinus L.) that is frequently misjudged as cannabis, were studied to contribute for prevention of illegal cannabis cultivation.

Key words--Cannabis sativa L.; Hibiscus cannabinus L.; morphology; germination

--Notes--

Effects of Combined Addition of Atovaquone and Lithium on the in Vitro Cell Growth of Pathogenic Yeast Candida albicans

Nobuko MINAGAWA,^* Mariko UEHARA, Shiori SEKI, Ayumi NITTA, and Kento KOGAWARA

Department of Biochemistry, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan

Atovaquone, an analog of ubiquinone, binds tightly to the ubiquinol oxidation site (Qo site) of parasite cytochrome bc₁ complex to inhibit electron transport at concentrations far lower than those at which the mammalian system is affected. The mode of action is thought similar to that of myxothiazol. To treat Pneumocystis jirovecii and Plasmodium falciparum infections, atovaquone has been used worldwide whereas it is unapproved in Japan. Since the pathogenic Candida species fungi seem resistant to atovaquone, this drug is not clinically available for candidosis, particularly deep mycosis. We examined the effects of atovaquone on cellular respiration and in vitro growth of C. albicans to explore a new therapeutic possibility for fungal infections. Atovaquone strongly inhibited glucose-dependent cellular respiration similarly to antimycin A, stigmatellin, and myxothiazol, specific bc₁ complex inhibitors. However, atovaquone suppressed glucose-dependent cell growth to a much lesser extent versus the comparator agents. When added alone, lithium exerted slight growth inhibition. The combined addition of lithium with atovaquone showed a significant increase in inhibition of growth. Although the way lithium acts synergistically with atovaquone remains to be elucidated, our results suggest a new therapeutic possibility of this combination for the treatment of candidosis.

Key words--atovaquone; Candida albicans; lithium

--Articles--

Search for the Subconsciousness of Hospital Pharmacists on Their Practices of Blood Drawing or Injection, and etc.

Masayoshi KOINUMA,^*,a Yoshiko MIYAZAKI,^b Tetsuro YUMOTO,^c Toru SATO,^d Shinichiro SUZUKI,^e Hirohumi NAKAJIMA,^f Motoki ARAKAWA,^a Katsuya KOIKE,^a Hideaki SATO,^g and Hitoshi NAKAMURA^a

^aCollege of Pharmacy Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan, ^bDepartment of pharmacy Takatsu Central Hospital, 1-16-7 Mizonokuchi, Takatsu-ku, Kawasaki, Kanagawa 213-0001, Japan, ^cDepartment of pharmacy General Sagami Kosei Hospital, 3429 Koyama, Sagamihara, Kanagawa 229-8555, Japan, ^dDepartment of pharmacy Kikuna Memorial Hospital, 4-4-27 Kikuna, Kouhoku-ku, Yokohama, Kanagawa 222-0011, Japan, ^eDepartment of pharmacy St. Marianna University School of Medicine, Yokohama-City Seibu Hospital, 1197-1 Yasashicho, Asahi-ku, Yokohama, Kanagawa 241-0811, Japan, ^fDepartment of pharmacy Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan, and ^gDepartment of pharmacy Ishinomaki Municipal Hospital, 1-7-20 Minamihamacho, Ishinomaki, Miyagi 980-0835, Japan

The purpose of this study was to clarify the subconsciousness of hospital pharmacists regarding them practicing drip infusion or blood drawing for therapeutic drug monitoring (TDM), etc. We conducted a mail-in survey targeting 476 randomly-selected hospital pharmacists. In our survey sheet we presented our “hypothetical condition” i.e., “that medical practices such as drip infusion or blood drawing for TDM by hospital pharmacists be legally allowed” and we asked them 23 items about the pros and cons of this hypothetical condition and its influence on medical practice. Then, using factor analysis, we searched for the subconsciousness of hospital pharmacists from their answers to the 23 items. We then analyzed the causal association between the factors extracted from the survey and the pros and cons of the “hypothetical condition” using logistic regression analysis. 47.7% of respondents agreed to the “hypothetical condition”. The results of this research provided 5 factors, consisting of “expectation of medical care and society”, “temperament of pharmacists”, “pharmacotherapy”, “employment”, and “medical team”. We understood from the result of logistic regression analysis that hospital pharmacists subconsciously had two kinds of expectation, i.e., expectation about medical care and society, and about qualitative improvement of pharmacotherapy, as their background when they decided to agree to themselves practicing drip infusion or blood drawing for TDM, etc.

Key words--hospital pharmacist; blood drawing; skill mix; questionnaire; exploratory data analysis

--Articles--

Analysis of Newly Distributed Designer Drugs Detected in the Products Purchased in Fiscal Year 2008

Nahoko UCHIYAMA,^a Norimasa MIYAZAWA,^b Maiko KAWAMURA,^a Ruri KIKURA-HANAJIRI,^a and Yukihiro GODA^*,a

^aNational Institute of Health Sciences (NIHS), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan, and ^bSaitama Institute of Public Health, 639-1 Kamiokubo, Sakura-ku, Saitama 338-0824, Japan

Thirty-two psychotropic substances were listed as designated substances (Shitei-Yakubutsu, 31 compounds and 1 plant) in Japan by the Pharmaceutical Affairs Law in April 2007 for preventing the abuse of these substances. Subsequently, other psychoactive compounds were also added to this category, 40 substances (classified as 12 tryptamines, 17 phenethylamines, 3 piperazines, 6 alkyl nitrites, 1 diterpene and 1 plant) are controlled as designated substances as of July 2009. However, new designer drugs are still distributed in illegal drug market according to the results of our annual survey. This study presents the analysis of four newly distributed designer drugs detected from two products, which were purchased from October 2008 to February 2009 in Japan. As the results of NMR, GC-MS and LC-MS analyses, three phenethylamine derivertives, 1-(2-fluorophenyl)-N-methylpropan-2-amine (N-Me-2-FMP), 1-(2,5-dimethoxy-4-isopropylsulfanylphenyl)propan-2-amine (ALEPH-4) and 1-(2,5-dimethoxy-4-nitrophenyl)propan-2-amine (DON) and a tryptamine derivative, N-ethyl-5-methoxy-N-propyltryptamine (5-MeO-EPT), were detected. N-Me-2-FMP and 5-MeO-EPT were newly identified in this study. Additionally, ALEPH-4 and DON were found as novel illegal drugs distributed in Japan.

Key words--psychotropic substance; NMR; GC-MS; LC-MS; designer drug; drug abuse

--Articles--

Safety Assessment regarding Use of Glucosamine Sulfate by Patients Whose Dietary Potassium Intake is Restricted

Yasuko ASAHINA,^a Satoko HORI,^b,c and Yasufumi SAWADA^*,c

^aGraduate School of Interdisciplinary Information Studies, ^bInterfaculty Initiative in Information Studies, and ^cGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Hyperkalemia is common in patients with renal disease, and is sometimes caused by dietary potassium intake. We aimed to determine and compare the content of potassium in nine brands of glucosamine supplements sold in the Japanese market and via the Internet. The potassium content was 0.165-3 mg per daily dose in Japanese products, which contained glucosamine hydrochloride or N-acetylglucosamine, while the content in foreign products, in which glucosamine was sulfated, was 197-280 mg. Our results show that the potassium content in glucosamine sulfate supplements can correspond to 20% of the maximum daily intake of potassium by patients on hemodialysis, because the products sometimes contain glucosamine as glucosamine sulfate potassium chloride for stabilization. Although it is not permitted to sell glucosamine sulfate as food in Japan, consumers can easily buy foreign products that contain glucosamine sulfate via the Internet, and those products rarely indicate the potassium content. Health professionals should pay attention to patients' use of glucosamine supplements, especially when patients' dietary potassium intake needs to be restricted.

Key words--glucosamine; potassium; hyperkalemia; dietary supplement