Vol.126, No. 9 (2006)

  The Pharmaceutical Society of Japan  

YAKUGAKU ZASSHI, 126(9),677-693, 2006


UVB-induced Skin Damage and the Protection/Treatment-Effects of a Novel, Hydrophilic γ-Tocopherol Derivative


Molecular Physiology, Kyoritsu University of Pharmacology, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan

Ultraviolet radiation is the major environmental cause of skin damage. Although only 0.5% of ultraviolet B (UVB) radiation reaches the earth, it is the main cause of sunburn and inflammation and the most carcinogenic constituent of sunlight. We investigated whether the topical application of a novel, water-soluble γ-tocopherol (γ-Toc) derivative, γ-tocopherol-N,N-dimethylglycinate hydrochloride (γ-TDMG), could protect against UV-induced skin damage. Topical pre- or postapplication of γ-TDMG solution significantly prevented sunburn cell formation, lipid peroxidation, and edema/inflammation that were induced by exposure to a single dose of UV irradiation. Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E2 (PGE2) levels seen after UV exposure were significantly suppressed by pre- or posttreatment with γ-TDMG. The increase in COX-2 activity was significantly inhibited by γ-TDMG, suggesting that the reduction in PGE2 concentration was due to the direct inhibition of COX-2 activity by γ-TDMG. The derivative strongly inhibited inducible nitric oxide synthase mRNA expression and nitric oxide production. With the application of γ-TDMG, the pigmentation in melanocytes was lightened and the increase melanin concentration was suppressed. γ-TDMG is converted to γ-Toc in the skin and has higher bioavailability than γ-Toc itself. These results suggest that γ-TDMG-derived γ-Toc acts as an antioxidant, antiinflammatory and antipigmentation agent. Our data further suggest that the topical application of γ-TDMG may be efficacious in preventing and reducing UV-induced skin damage in humans.

Key words--antioxidant; inflammation; pigmentation; skin photodamage; UVB irradiation

YAKUGAKU ZASSHI, 126(9),695-709, 2006


Mechanisms of Hypertension in the Central Nervous System

Takao KUBO

Showa Pharmaceutical University, 3-chome, Higashi-Tamagawagakuen, Machida City 194-8543, Japan

This article reviews studies by the author on central mechanisms of hypertension. Spontaneously hypertensive rats (SHR) have been developed as a rat model of genetic hypertension, and central acetylcholine has been implicated in hypertension in SHR. The rostral ventrolateral medulla (RVL), a major source of efferent sympathetic activity, has cholinergic pressor systems. The release of acetylcholine is enhanced in the RVL of SHR, leading to hypertension. The alteration of the RVL cholinergic system in SHR results from enhanced angiotensin systems in the anterior hypothalamic area (AHA). Angiotensin II-sensitive neurons are present in the AHA and they are tonically activated by endogenous angiotensins. The basal activity of AHA angiotensin II-sensitive neurons is enhanced in SHR, mainly due to enhanced sensitivity of AHA neurons to angiotensin II. The AHA angiotensin system is also responsible for hypertension induced by emotional stress and central Na+ increases. These findings suggest that the AHA angiotensin system may play a critical role in the development of hypertension.

Key words--angiotensin; hypothalamus; hypertension; acetylcholine; medulla oblongata; genetic hypertension

YAKUGAKU ZASSHI, 126(9),711-721, 2006


Claudin as a Novel Target for Drug Delivery System


Department of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita City 565-0871, Japan

Recent remarkable progress in genomic novel drug discovery enables us to prepare drug candidates with tremendous diversity in a high-throughput-manner. In clinical use of these candidates, they should be effectively delivered to a target-tissue in body. But delivery systems suitable for the high-throughput discovery of drugs have never been established. Tight junctions (TJs) play a pivotal role in compartmentation of each tissues and maintenance of their intra-circumstances. Claudin, a membrane protein with four trans-membrane domains, have recently found to be responsible for the barrier-function of TJs. Claudin is constituted of 24 family members, and expression profiles and barrier-function of claudin differ interestingly among the family members. These findings indicate that a modulator of the unique barrier-function of claudin may be used for drug delivery. In this respect, we have investigated whether a claudin is a target for drug delivery. A claudin modulator (C-terminal fragment of Clostridium perfringens enterotoxin, C-CPE) had 400-fold jejunal absorption-enhancing activity to a clinically used absorption-enhancer, and interaction between C-CPE and claudin was essential for the enhancing activity. We have already prepared a screening system for claudin-targeting molecule. Now we are performing functional domain mapping of C-CPE, and we will attempt to prepare a various type of claudin modulator in a future. In the current review, I introduce our recent works on development of a novel strategy for drug delivery system using claudin modulator, and I discuss also possibility of claudin modulator in drug delivery system.

Key words--claudin; tight junction; Clostridium perfringens enterotoxin; paracellular route

YAKUGAKU ZASSHI, 126(9),723-735, 2006


Pharmacokinetic Study of Cancer Chemotherapy

Tatsuya ITOH

Department of Pharmacy, Sapporo Social Insurance General Hospital, 6-2-1 Atsubetsu-chuo 2-jyo, Atsubetsu-ku, Sapporo City 004-8618, Japan

We reported that the rate of conversion of lactone to carboxylate forms of irinotecan (CPT-11) and its metabolites plays a major role in the biliary excretion of these compounds. Sulfobromophthalein partially inhibited the secretion of SN-38-glucronide into the gastrointestinal lumen, whereas little change was seen in that of active metabolite SN-38. Co-administration of sulphobromophthalein with CPT-11 might lower the late-onset gastrointestinal toxicity observed during treatment with CPT-11 without lowering anticancer activity. In the ileum, the level of transport in the direction form the serosal layer to mucosal layer was significantly greater than that in the direction form the mucosal layer to serosal layer, whereas a significant difference was not observed in the jejunum. This secretory transport required metabolic energy was diminished by sulfobromophthalein. A specific transport system plays a major role in the secretion of SN-38 and that this secretory transport system predominantly exists in the ileum. Uptake of SN-38 was significantly reducted at 4°C. Baicalin inhibited the uptake of SN-38. A specific transport system mediates the uptake of SN-38 across the apical membrane in Caco-2 cells. Inhibition of this transporter would be a useful means for reducing late-onset diarrhea.

Key words--irinotecan (CPT-11); SN-38; sulfobromophthalein; Caco-2 cells; transporter

YAKUGAKU ZASSHI, 126(9),737-745, 2006


A Study on the Highly Efficient Synthesis and Pharmaceutical Evaluation of PET Radiopharmaceuticals for the Clinical Application


Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Positron Emission Tomography (PET) is an advanced non-invasive technology used in the field of nuclear medicine for clinical diagnosis using radiotracers labeled with short-lived positron emitting radionuclides such as 11C (half-life: 20.4 min), 13N, 15O and 18F. The present study describes an efficient rapid synthesis method for [11C]Phosgene ([11C]COCl2) which is an important potential precursor for preparation of PET radiopharmaceuticals. Catalytic oxidation of [11C]CCl4 using Fe2O3 powder mixed with Fe granules as an oxidizing agent was newly accomplished with a development of fully automated synthetic apparatus. Utilization of produced [11C]COCl2 provided a substantial synthesis of [2-11C]thymine as a key intermediate for preparation of [2-11C]thymidine, a PET tracer to evaluate cellular proliferation. Direct ring closure reaction of the alkali metal salt of β-(N-benzoyl-amino)methacrylamide with [11C]COCl2 readily proceeded under mild conditions to afford [2-11C]thymine in fair yield reproducibly. By way of further application, a useful PET ligand for β-adrenoreceptors, S-(−)-[11C]CGP-12177 (CGP) was synthesized in markedly high yield with high specific activity and radiochemical purity. CGP for intravenous injection was prepared in 25 min after EOB with a yield of 1.5±0.2 GBq. These results of quality control tests demonstrated that CGP preparation is suitable for routine clinical use. Thus, CGP-PET study has been newly added to clinical PET for cardiac functional investigation in Hokkaido University Hospital.

Key words--[11C]phosgene; S-(−)-[11C]CGP-12177; [2-11C]thymine; Positron Emission Tomography

YAKUGAKU ZASSHI, 126(9),747-755, 2006


Development of Anti-dementia Drugs Related to Neurotrophic Factors

Yutaro OBARA

Department of Cellular Signaling and 21st Century COE Program “CRESCENDO”, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai City 980-8578, Japan

Neurotrophic factor-like substances and inducers of neurotrophic factor biosynthesis have enormous therapeutic potential for serious neuronal diseases such as Alzheimer's disease. Here, we discuss about the pharmacological effects of scabronines and β-eudesmol as promising candidates of leading compounds against the dementia. In addition, we discuss about the signaling pathway of nerve growth factor and cyclic AMP in order to seek the signaling molecules as targets of drug development.

Key words--neurotrophic factor; nerve growth factor (NGF); cyclic AMP (cAMP); scabronine; β-eudesmol

YAKUGAKU ZASSHI, 126(9),757-766, 2006


Development of Environmentally Benign Oxidations Using Hypervalent Iodine (III) Reagents

Toshifumi DOHI

Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City 565-0871, Japan

We have synthesized a novel, nonpolymer-supported recyclable hypervalent iodine (III) reagent, 1,3,5,7-tetrakis[4-(diacetoxyiodo)phenyl]adamantane 3a and its derivatives 3b, c and utilized them in environmentally benign oxidations. The new reagents 3a-c mediate a wide range of oxidative transformations with efficiencies similar to those of conventional reagents, phenyliodine (III) diacetate (PIDA), pheyliodine (III) bis (trifluoroacetate) (PIFA), and (hydroxyl(tosyloxy)iodo). benzene (HTIB), and have higher reactivity compared with polymer-supported recyclable reagents such as poly(diacetoxyiodo)styrene (PDAIS) and poly{bis(trifluoroacetoxy)iodo}styrene (PBTIS). In all cases, tetraiodide 4 was recovered nearly quantitatively in a pure form after simple workup, i.e., filtration. Reoxidation of 4 to 3a with m-chloroperbenzoic acid also proceeded quantitatively, without loss of oxidative activity. Recyclable 3a-c are used in various organic solvents as well as water, and thus mild and clean oxidation of alcohols in water has been achieved using 3a. A facile synthesis of aldehydes from primary alcohols has also been demonstrated using a dual recycling strategy, with 3a and recyclable 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO).

Key words--hypervalent iodine, oxidations, recycling, supramolecular structures, aqueous media

YAKUGAKU ZASSHI, 126(9),767-778, 2006


Clinicopharmacological Study of Gastrointestinal Drugs from the Viewpoint of Postmarketing Development

Hiroki ITOH

Department of Pharmacy, Oita University Hospital, 1-1 Hasama-machi, Yuhu City, Oita 879-5593, Japan

Pharmaceutical development starts with the discovery of a new compound. Drugs become commercially available after non-clinical and clinical studies, but processes that take place after marketing are also important for pharmaceutical development. In recent years, use of the phrase “Ikuyaku” meaning postmarketing development has become more common. Sometimes, the proper usage, indications and harmful effects of a drug are discovered only after it becomes commercially available and is administered to many patients. Hence, pharmacists need to actively perform postmarketing studies to reveal the true nature of drugs. In the present clinicopharmacological study, we investigated the effects of histamine H2 receptor antagonists (H2-RAs) on the plasma concentrations of gastrointestinal peptides from the viewpoint of postmarketing development. First we established an enzyme immunoassay for secretin, which is involved in gastrointestinal motility. Then we used this and existing peptide assays to investigate the above-mentioned issues. Ranitidine and nizatidine increased the plasma concentration of motilin. It is believed that the plasma concentration of Ach is elevated by ranitidine and nizatidine, which possesses an anti-AchE activity, and that the increased the plasma concentration of Ach facilitated release of motilin, elevating the plasma concentration of motilin. When compared to the placebo, lafutidine significantly increased the plasma concentration of CGRP (calcitonin gene-related peptide) and substance P. Furthermore, released CGRP stimulated CGRP1 receptors to facilitate secretion of somatostatin. Therefore, lafutidine appears to protect the gastric mucosa and regulate gastrointestinal motility. The same results were obtained with ranitidine and nizatidine. While H2-RAs have a common function in suppressing the secretion of gastric acid, they do not exhibit the same effects on factors related to recurrence of peptic ulcer, such as gastrointestinal motility and blood flow in the gastrointestinal mucosa. Hence, measuring the plasma concentration of gastrointestinal peptides can be used to estimate the effects of drugs on gastrointestinal motility. From the viewpoint of postmarketing development, we are in the process of establishing indicators for the proper usage of pharmaceutical drugs. Pharmacists need to closely follow and monitor adverse reactions. In order to further improve monitoring of drug therapy, it will be necessary to assess not only the blood concentrations of drugs, but also biological reactions to the drugs. Since the levels of peptides reflect the clinical efficacy of gastrointestinal drugs, measuring peptide levels appears to be useful for selecting appropriate drugs.

Key words--peptide; enzyme immunoassay; histamine H2 receptor antagonists

YAKUGAKU ZASSHI, 126(9),779-787, 2006


Synthesis and Optical Properties of the Helical Oligonaphthalenes

Kazuto TAKAISHI,* Kazunori TSUBAKI, Hiroyuki TANAKA, Masaya MIURA, and Takeo KAWABATA

Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan

We have developed an efficient synthesis method for optically active oligonaphthalenes (from 2 mer to 16 mer), which are connected at their 1,4-positions, under oxidative homo coupling with a stoichiometric amount of CuCl2 and amines. The absolute configuration of the newly formed axis bond was determined based on the CD spectra of oligonaphthalenes with 1) two pyrene rings on the central naphthalenes or 2) two tetraphenylporphyrins (TPP) on the top and bottom naphthalenes. The fluorescence quantum yields increased as the number of naphthalene units increased in methoxy derivatives 10-12, and the intramolecular energy transfer quantum yields of bispyrene derivatives 7-9 were around 20% regardless of the number of naphthalene units. Furthermore, the hexadecanaphthalene derivative 4b with two TPPs exhibited a clear exciton coupling over an interchromophore distance to ca. 66 Å.

Key words--oligonaphthalenes; bottom-up synthesis; long-range exciton coupling; energy transfer

YAKUGAKU ZASSHI, 126(9),789-793, 2006

--Regular Articles--

Preparation of N-Succinyl-chitosan and Their Physical-Chemical Properties as a Novel Excipient

Chengyun YAN,a,b Dawei CHEN,*,a Jiwei GU,b Haiyang HU,a Xiuli ZHAO,a and Mingxi QIAOa

aBox 42, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016 Liaoning Provice, P. R. China, and bCollege of Chemistry & Pharmacy, Jiamusi of University, Jiamusi 154000 Heilongjiang Provice, P. R . China

The aim of this work is to prepare N-succinyl-chitosan (Suc-Chi) and measure physical-chemical properties for Suc-Chi as excipients. Suc-Chi were prepared via ring-opening reactions with succinic anhydride in Dimethyl Sulfoxide system. The physical-chemical properties of Suc-Chi, such as the degree of substitution (DS), solubility, isoelectric point (pI), glass transition temperature (Tg), partition coefficient (Papp) and zata potential were detected respectively in order to evaluate their possibility as drug carriers. We obtained Suc-Chi DAC-90 (DS=0.33) and the data of physical-chemical properties for the product. The knowledges of physical-chemical properties for Suc-Chi are valuable for basic or applied purposes in biomedical and pharmaceutical sciences stabilization.

Key words--N-succinyl-chitosan; preparation; physical-chemical properties; excipients

YAKUGAKU ZASSHI, 126(9),795-804, 2006

--Regular Articles--

Antiamnesic Effects of Desmodium gangeticum in Mice

Hanumanthachar JOSHI,*,a and Milind PARLEb

aDepartment of Pharmacognosy, SET'S College of Pharmacy, S.R. Nagar, Dharwad-580 002 Karnataka, India and bDivision of Pharmacology, Department of Pharmaceutical Sciences, Guru Jambheshwar University, Hisar, Haryana, India

Dementia is a mental disorder characterized by loss of intellectual ability sufficiently severe enough to interfere with one's occupational or social activities. Desmodium gangeticum commonly known as Salparni, is widely used in ayurveda for the treatment of neurological disorders. The present work was designed to assess the potential of aqueous extract of D. gangeticum (DG) as a nootropic agent in mice. DG (50, 100 and 200 mg/kg, p.o.) was administered for 7 successive days to both young and older mice. Exteroceptive behavioral models such as elevated plus maze and passive avoidance paradigm were employed to evaluate learning and memory. Scopolamine (0.4 mg/kg, i.p.) induced amnesia and ageing induced amnesia were the interoceptive behavioral models. To delineate the mechanism by which DG exerts nootropic activity, the effect of DG on whole brain AChE activity was also assessed. Piracetam (200 mg/kg, i.p.) was used as a standard nootropic agent. Pretreatment with DG (50, 100 and 200 mg/kg p.o.) for seven successive days significantly improved learning and memory in mice and reversed the amnesia induced by both, scopolamine (0.4 mg/kg, i.p.) and natural ageing. DG also decreased whole brain acetyl cholinesterase activity. Hence, D. gangeticum appears to be a promising candidate for improving memory and it would be worthwhile to explore the potential of this plant in the management of dementia and Alzheimer disease.

Key words--acetylcholine; nootropic; D. gangeticum; memory

YAKUGAKU ZASSHI, 126(9),805-809, 2006


Optimum Preparation of Levocarnitine Chloride Solution in the Hospital Pharmacy

Hiroaki TANAKA,*,a,b Masato ASAKURA,a Chiaki DOI,a Noriyasu FUKUOKA,a Eiji TAMAI,b Shigeru MIYATA,b Osamu MATSUSHITA,b Akinobu OKABE,b Kiyoshi NEGAYAMA,c and Hitoshi HOUCHIa

aDepartments of Pharmacy, and cClinical Laboratory, Kagawa University Hospital and bDepartment of Microbiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan

Levocarnitine chloride is used for the therapeutic purpose of levocarnitine deficiency. For infants, however, levocarnitine chloride tablets must be crushed to avoid difficulties associated with swallowing, and also to administer an appropriately low dosage. Since the tablet is extremely hygroscopic and sour, it is dissolved in water containing simple syrup after crushing. In this study we investigated the stability of the drug after dissolution to optimize its preparation for clinical use. It was shown to be stable for at least 90 days after preparation, and microbes did not grow in 1-10% (w/v) solutions (pH 2.0-2.5) regardless of the presence or absence of simple syrup. Furthermore, the autoclaved levocarnitine chloride solution was as stable as the non-autoclaved one. In conclusion, the method employed in our hospital for the preparation of levocarnitine chloride for infants is appropriate and is recommended as a standard medicine supply method among different facilities.

Key words--levocarnitine chloride; levocarnitine deficiency; preparation; infants; optimum preparation

YAKUGAKU ZASSHI, 126(9),811-814, 2006


Determination of Chlorogenic Acid in Rat Plasma by High Performance Chromatography after Peritoneal Administration of Compound Daqingye Injection

Bo YUAN,* Mingxi QIAO, Haiyan XU, Lei WANG, and Famei LI

School of Pharmacy P.O. Box 42, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016 Liaoning Province, P.R. China

A simple and sensitive high performance liquid chromatographic method has been developed for the determination of chlorogenic acid (3-O-caffeoyl-D-quinic acid) in rat plasma and applied to its pharmacokinetic study in rats after peritoneal administration of compound Daqingye injection. Plasma samples are extracted with perchloric acid. HPLC analysis of the chlorogenic acid is performed on a C18 reversed-phase column using methanol-water (80: 20, v/v, pH 2.8) as mobile phase with UV detector set at 327 nm. The standard curves are linear in the range of 0.200-10.0 μg/ml (r=0.9982). The inter- and intra-day precision (relative standard deviation) was less than 9% and the accuracy (relative error) was less than 10%. The limit of quantitation was 0.200 μg/ml. The plasma concentration of chlorogenic acid shows a Cmax of 7.53±0.52 μg/ml at 13.33±4.00 min with a t1/2 of 59.10±5.42 min.

Key words--Daqingye; chlorogenic acid; HPLC

YAKUGAKU ZASSHI, 126(9),815-823, 2006


The Analysis of the Chemical Drugs among Structural Isomer

Kayo DOI,*,a Maki MIYAZAWA,a Hisashi FUJII,b and Takashi KOJIMAa

aKanagawa Prefectural Institute of Public Health, 1-3-1 Shimomachiya, Chigasaki City 253-0087, Japan and bKanagawa Industrial Technology Center, 705-1 Shimoimaizumi, Ebina City 243-0435, Japan

Drugs that have a pharmacological effect similar to legal drugs such as narcotics and stimulants are available in the market and widely used. 5-methoxy-N,N-di-iso-propyl-tryptamine (5MeO-DIPT) and α-methyl-tryptamine (AMT) were categorized as narcotics and were specified as legal drugs in April 2005, and also 2,5-dimethoxy-4-n-propylthiophenethylamine (4C-T-7) and N-methyl-α-ethy-3,4-methylenedioxy-phenethylamine (MBDB) were categorized as narcotics and were specified as legal drugs in April 2006, in Japan. We are analyzing these chemical drugs by investigating the market research. It is recognized that during the analysis of chemical drugs, drugs that resemble a structural isomer of a target substance, such as 5MeO-DIPT and 5-methoxy-N,N-di-n-propyl-tryptamine (5MeO-DPT) or 4C-T-7 and 2,5-dimethoxy-4-iso-propylthiophenethylamine (4C-T-4), should be distinguished. The results of TLC, IR, GC-MS and HPLC analyses were compared. 5MeO-DIPT and 5MeO-DPT could be distinguished by TLC and HPLC analyses, but not by IR and GC-MS analysis. The drugs 4-hydroxy-N-methyl-N-iso-propyl-tryptamine (4HO-MIPT) and 4-hydroxy-N,N-di-ethyl-tryptamine (4HO-DET) or could not be distinguished. Moreover, the isomers of 4-hydroxy-N-methyl-N-n-propyl-tryptamine (4HO-MPT) was not found to be present. Thus, we have demonstrated that the chemical drug could be distinguished from each other, and we have also shown that NMR data is essential for the analysis.

Key words--abuse drug; structural isomerism; 5-methoxy-N,N-di-iso-propyl-tryptamine; 5-methoxy-N,N-di-n-propyl-tryptamine; chemical drug

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