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Volume 131, Issue 2
Displaying 1-21 of 21 articles from this issue
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Symposium Reviews
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Masaaki AKAGI, Hiroyuki FUKUIArticle type: Foreword
2011 Volume 131 Issue 2 Pages 169
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
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Hiroyuki MIZUGUCHI, Yoshiaki KITAMURA, Yuto KONDO, Wakana KURODA, Haru ...Article type: Review
2011 Volume 131 Issue 2 Pages 171-178
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSTherapeutics targeting disease-sensitive genes are required for the therapy of multifactorial diseases. There is no clinical report on therapeutics for allergic disease-sensitive genes. We are focusing on the histamine H1 receptor (H1R) as a sensitive gene. H1R mediates allergy histamine signals. H1R is a rate-limiting molecule of the H1R signal because the signal is increased with elevated receptor expression level. We discovered that the stimulation of H1R induced H1R gene expression through PKCδ activation, resulting in receptor upregulation. The mechanism of H1R gene expression was revealed to play a key role in the receptor expression level in studies using cultured HeLa cells and allergic rhinitis model rats. Preseasonal prophylactic treatment with antihistamines is recommended for the therapy of pollinosis. However, the mechanism of the therapy remains to be elucidated. We demonstrated that repeated pretreatment treatment with antihistamines in the allergic rhinitis model rats resulted not only in improvement of symptoms but also in suppressed elevation of H1R mRNA levels in the nasal mucosa. A clinical trial was then initiated. When symptoms and H1R mRNA levels in the nasal mucosa of pollinosis patients with or without preseasonal prophylactic treatment with antihistamines were examined, both symptoms and high levels of H1R mRNA were significantly improved in treated compared with untreated patients. These results strongly suggest that H1R is an allergic disease-sensitive gene.
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Noriyasu HIRASAWA, Kazuo OHUCHIArticle type: Review
2011 Volume 131 Issue 2 Pages 179-184
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSWe established a novel dermatitis model in mice earlobes and analyzed the roles of histamine using specific antagonists for histamine receptors. After sensitization with picryl chloride (PiCl) by painting it on the earlobes of cyclophosphamide-treated mice, 12-O-tetradecanoylphorbol 13-acetate (TPA) was painted twice at the same site, and then allergic inflammation was induced by painting with PiCl. Histamine antagonists and cyclosporin A were administered i.v. The application of TPA shifted the PiCl-induced allergic inflammation from a delayed-type response to a biphasic response and increased the infiltration of eosinophils and mast cells at the inflammatory site. In this model, the PiCl-induced increase in the thickness of the earlobe in the immediate phase was suppressed by the histamine H1 antagonist pyrilamine. In contrast, the increase in the swelling in the late phase and the infiltration of eosinophils were suppressed by the H3/H4 antagonist thioperamide. The inhibitory effect of the combined treatment with pyrilamine and thioperamide on TPA-modified contact dermatitis was as potent as that of cyclosporin A. Histamine plays significant roles in early-phase swelling via H1 receptors and in late-phase swelling via H3/H4 receptors in this TPA-modified allergic dermatitis model.
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Kohei YAMAUCHI, Toshiki SHIKANAI, Yutaka NAKAMURA, Hitoshi KOBAYASHI, ...Article type: Review
2011 Volume 131 Issue 2 Pages 185-191
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSHistamine has been reported to play an important role in pathogenesis of bronchial asthma. However, H1-blockers are not recommended as the first drug for asthma therapy in the guidelines. Histamine may play various roles in allergic airway inflammation through the H1 receptor (H1R), H2R, and H4R in immune cells including T lymphocytes and dendritic cells. We therefore evaluated its role in allergic airway inflammation with the use of histamine-deficient mice. The results suggested that histamine plays a role in the prevention of goblet cell hyperplasia. Organic cation transporter-3 (OCT-3) is thought to be a transporter of histamine. Polymorphism of OCT-3 {R120R (T/C)} was associated with the severity of asthma. Recently, it has been proposed that both asthma and allergic rhinitis should be treated as a single airway disease. Comorbidity of asthma and allergic rhinitis is very high (70-80%) and they share similar allergic inflammation. H1-blockers are recommended as first-line drugs to treat allergic rhinitis in the guidelines. Therefore H1-blockers are strongly recommended for patients with both asthma and allergic rhinitis.
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Yasuo TSUTSUMI, Yasuo YOSHIOKAArticle type: Foreword
2011 Volume 131 Issue 2 Pages 193-194
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
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Akihiko HIROSE, Atsuya TAKAGI, Tetsuji NISHIMURA, Hiroyuki TSUDA, Yosh ...Article type: Review
2011 Volume 131 Issue 2 Pages 195-201
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSManufactured nanomaterials are the most important substances for the nanotechnology. The nanomaterials possess different physico-chemical properties from bulk materials. The new properties may lead to biologically beneficial effects and/or adverse effects. However, there are no standardized evaluation methods at present. Some domestic research projects and international OECD programs are ongoing, in order to share the health impact information of nanomaterails or to standardize the evaluation methods. From 2005, our institutes have been conducting the research on the establishment of health risk assessment methodology of manufactured nanomaterials. In the course of the research project, we revealed that the nanomaterials were competent to cause chronic effects, by analyzing the intraperitoneal administration studies and carcinogenic promotion studies. These studies suggested that even aggregated nanomaterials were crumbled into nano-sized particles inside the body during the long-term, and the particles were transferred to other organs. Also investigations of the toxicokinetic properties of nanomaterials after exposure are important to predict the chronically targeted tissues. The long lasting particles/fibers in the particular tissues may cause chronic adverse effects. Therefore, focusing on the toxicological characterization of chronic effects was considered to be most appropriate approach for establishing the risk assessment methods of nanomaterials.
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Shin-ichi TSUNODAArticle type: Review
2011 Volume 131 Issue 2 Pages 203-207
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSRecently, the number of applications of nanomaterials in medicine, cosmetics and food to which we are directly exposed has been expanding rapidly. The safety of such nanomaterials has not been well assessed, because nanomaterials have been considered as safe as common larger sized materials which are known not to be absorbed by the body. Therefore, WHO and OECD are collecting safety information on nanomaterials with a view to regulation of their use. Although assessment of in vivo behaviors of nanomaterials, (i.e., absorption and distribution, and correlation analysis with hazard information) is urgently needed, such research has not yet been undertaken. In this regard, using amorphous silica particles as model nanomaterials, we are starting to study safety, in vivo behavior and their correlation; silica particles are often used in cosmetics and foods and also, downsized particles are rapidly becoming available. In our study, we have found that silica particles below 100 nm in diameter show significantly different characteristics in in vivo behavior and biological effects i.e., penetration through skin and distribution to brain. Here, I addressed the importance of studies in physicochemical characteristics, kinetic behaviors, and biological effects of nanomaterials below 100 nm in size, to ensure their safety.
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Tomoaki YOSHIKAWAArticle type: Review
2011 Volume 131 Issue 2 Pages 209-213
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSWith recent developments in nanotechnology, nanomaterials have been successfully employed in various industrial applications such as medicine and cosmetics. Nanomaterials demonstrate useful properties such as electronic reactivity and tissue permeability that are absent in micromaterials. Thus, it is anticipated that nanomaterials will be developed as innovative materials in medicine and the cosmetics industry. However, these innovative properties may be accompanied by unknown biological responses that could not have been detected by conventional toxicity assays. To promote industrial development and to establish an affluent society that enjoys only the benefits of nanomaterials, we urgently need to gather information on the properties and biological effects of nanomaterials, and to establish appropriate standard safety evaluation methods. We are therefore analyzing the association of nanomaterial interactions with macromolecules (proteins, DNA etc.) and biodistribution using nanosilicas (nSP) as a standard nanomaterial. The results of this study are useful for extrapolation to other nanomaterials and to establish practicable strategies for the development of prediction methods for nanomaterials.
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Yasuhiro ABEArticle type: Review
2011 Volume 131 Issue 2 Pages 215-219
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSRecently, nanomaterials (NMs) showing useful properties such as controlled release and tissue permeability have been developed for practical use as medicine and cosmetics. On the other hand, because NMs possess innovative properties, kinetics, and biological effects distinct from those of micro size bulk materials, the potential harmful effects of NMs on humans are raising concerns about their safety. Therefore, there is an urgent need for risk assessment of NMs. To achieve this, it is most important to analyze the relationship between physicochemical properties such as particle size and surface characteristics, cellular distribution and biological effects, allowing prediction and avoidance of risk in using NMs. However there is little information about association of nanomaterial properties with kinetics (exposure, absorption, distribution, and excretion). In this respect, we have not only collected hazard information on NMs but have also analyzed the linkage between silica particle size and their hazards. We have demonstrated that NM with a diameter of under 100 nm can penetrate the stratum corneum of mouse skin and are taken up by living cells such as keratinocytes and Langerhans cells. Additionally, NM taken up by cells entered the nucleus, indicating the risk of genotoxicity. In this review, we would like to discuss the relationship between particle size, intracellular distribution, and hazard effect.
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Yasuo YOSHIOKAArticle type: Review
2011 Volume 131 Issue 2 Pages 221-224
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSA diverse array of nanomaterials such as nanosilicas and carbon nanotubes are in widespread use due to the development of nanotechnology. Nanomaterials are already being applied in universal fields such as electronics, sunscreens, cosmetics, and medicine, because they have unique physicochemical properties such as high conductivity, strength, durability, and chemical reactivity. The advent of nanomaterials has also provided extraordinary opportunities for biomedical applications. However, the increasing use of nanomaterials has raised public concern about their potential risks to human health. In particular, recent reports have indicated that carbon nanotubes induced exaggerated inflammation and mesothelioma-like lesions in mice. However, few studies have examined the immunotoxicity of nanomaterials and it is essential to progress studies on the immunotoxicity of nanomaterials to ensure their safety. In this regard, we have attempted to elucidate the pharmacodynamics and immunotoxicity of nanomaterials, in order to develop novel safe nanomaterials and to establish scientifically based regulations. In this review, we would like to introduce our data on the immunotoxicity of nanosilicas, especially the relationship between physical properties (primary grain size, configuration and surface charge), pharmacodynamics of these materials, and their immunotoxicity. We consider that our study will improve the quality of human life by safely using nanomaterials, which can benefit society in general.
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Kazuya NAGANOArticle type: Review
2011 Volume 131 Issue 2 Pages 225-228
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSNanomaterials acquire revolutionary functions such as anti-inflammatory and anti-viral effects by increasing surface area per unit weight, due to the reduction to nano size. Such nanomaterials are rapidly put to practical use without safety evaluation. This is because it is widely assumed that nanomaterials are merely of the same molecular composition as existing materials of more than submicron size, and that nanomaterials cannot be absorbed from the digestive tract or skin as is the case with existing materials of more than submicron size. On the other hand, as was the case with thalidomide, evidence shows that fetuses and infants are affected more than adults by a variety of environmental toxins, because of physiological immaturity. Thus, placental or breast milk-mediated exposure to nanomaterials may possibly induce unexpected biological effects. To our knowledge, however, no studies have examined effects of pregnant animal exposure to nanomaterials on transitivity to placenta or infants, or on maintenance of pregnancy. Therefore, using nanosilica particles (nSPs) employed as additives in cosmetics and foods, we will report on the efficiency of transitivity of nSPs of various diameters to the circulation through the placental barrier after nanomaterial exposure and the risks of nSP exposure to pregnant mice. In this review, I will discuss the development of safety in nanomaterials and the maintenance of good health.
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Ken TAKEDA, Yusuke SHINKAI, Ken-ichiro SUZUKI, Shinya YANAGITA, Masaka ...Article type: Review
2011 Volume 131 Issue 2 Pages 229-236
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSIn order to discuss the health effects of nanomaterials, we cannot disregard the research on the health effects of airborne particulates. It is said that many of the fine or ultrafine particles in airborne particulates originate from diesel vehicles in metropolitan areas. The results of not only animal experiments but many epidemiologic surveys and volunteer intervention experiments in humans are reported on the health effects of particles. Although the health effects of the particulate matter particle sizes below 10 μm (PM10) were investigated in the initial studies, recently even smaller particles have come to be regarded as questionable and research of the health effects of the minute particulate matter below 2.5 μm (PM2.5) has been done. However, our recent study about maternal exposure to diesel exhaust suggests that health effect study of PM0.1, particles below 0.1 μm (100 nm), namely nanoparticles, is necessary from now on. We are proceeding with the study of the health effects of various types of intentionally produced nanomaterials such as carbon black, carbon nanotube, fullerene and titanium dioxide, examining in particular their influence on next generation. Although there are differences in the sites affected and the seriousness of the damage, basically similar findings to DEPs mentioned above are being discovered in research on nanomaterials. Regardless of dosage and administration method, such as inhalation, endotracheal administration, nasal drip and subcutaneous administration, once nanomaterials enter the bloodstream of a pregnant mother mouse, they move to the offspring and have effects on them. The effects may appear as various symptoms in the process of growth after birth, and can sometimes lead to the onset and aggravation of serious diseases.
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Ryuichi HASEGAWA, Masaru IWASAKIArticle type: Foreword
2011 Volume 131 Issue 2 Pages 237-238
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
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Yoshiro SAITOArticle type: Review
2011 Volume 131 Issue 2 Pages 239-246
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSAnti-cancer drugs have relatively low effective rates and high frequencies of adverse reactions, occasionally leading to cessation of their treatments. Use of pharmacogenomic (PGx) information could be able to select the patients with high-response and less-adverse reactions, resulting in increase of patients' QOL and proper use of drugs. We have been collaborating with National Cancer Center for PGx analysis of anti-cancer drugs including irinotecan and gemcitabine in Japanese cancer patients. Irinotecan, now used for treatments of many cancers, is metabolically activated to SN-38 and then inactivated to SN-38 glucuronide by a UDP-glucuronosyltransferase UGT1A1. In the UGT1A1 gene, two representative genetic polymorphisms, *28 and *6, were detected at 0.138 and 0.167, respectively in 177 Japanese cancer patients. When the patients were homozygotes of *28 or *6, or compound heterozygotes of them, statistically significant decreases were observed in the SN-38 glucuronidation activity and increases in the rate of severe neutropenia, compared to those in the patients without *28 or *6. Our results and papers were cited in the Japanese package inserts of irinotecan. Gemcitabine was inactivated by cytidine deaminase (CDA) into 2′-2′-difluorodeoxyuridine. A CDA polymorphism 208G>A (Ala70Thr) was detected at 0.037 frequency in 256 Japanese cancer patients and associated with reduced gemcitabine clearance as well as increased frequency of severe neutropenia. In the 4 patients suffered from very severe bone marrow toxicities, 3 patients were homozygous CDA*3, suggesting that this polymorphism is exquisite for predicting severe adverse reactions by gemcitabine in Japanese.
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Kan CHIBA, Kaori MORIMOTOArticle type: Review
2011 Volume 131 Issue 2 Pages 247-253
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSThis review summarizes genetic factors predisposed to statin-induced rhabdomyolysis. The first genetic risk factor of statin myopathy uncovered by genome-wide analysis of single nucleotide polymorphisms was the common variant of SLCO1B1 gene. Analysis of 30000 genetic markers in 85 patients with myopathy induced by high-dose simvastatin showed a strong association with 521T>C polymorphism of SLCO1B1. Another study also showed that this variant of SLCO1B1 has a significant association with myopathy in patients taking pravastatin or atorvastatin although the number of patients analyzed was limited. In addition to SLCO1B1, recent studies suggested that variants of genes encoding transporters (ABCG2 and ABCB1) and metabolic enzymes (CYP2C8 and UGT1A3) involved in the disposition of statins, and those involved in the metabolic muscle disease (glycogen storage disorders, carnitine palmitoyl-2 deficiency and myoadenylate deaminase deficiency) are also risk factors of statin-induced myopathy. These genetic factors may provide predisposition testing for statin-induced rhabdomyolysis.
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Nahoko KANIWAArticle type: Review
2011 Volume 131 Issue 2 Pages 255-261
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSMost of adverse drug reactions (ADRs) occur as an extension of pharmacological effects. They occur dependently on their blood concentrations and can be potentially reduced by controlling their dose. On the other hand, ADRs categorized as Type B usually occur irrelevantly to their pharmacological effects at different organs from their target, and are often life-threatening and unpredictable. The incidences of Type B ADRs are very low. Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are delayed allergic reactions in which T-cells are involved and categorized as Type B ADRs. Recent progress of pharmacogenomic studies has revealed that particular types of human leukocyte antigen (HLA) class I antigens have strong associations with severe cutaneous adverse reactions and that the associations are specific to causative drugs, phenotypes of adverse reactions and ethnic groups. We established a research group in 2006 with professionals of pharmacogenomics, dermatologists, ophthalmologists and psychiatrists to explore genetic biomarkers associated with Japanese SJS/TEN patients. To date, we have collected more than 100 Japanese SJS/TEN patients through participating institutes and a case-collecting system covering all over Japan constructed by us. No carriers of HLA-B*1502 which was reported to have extremely strong association with carbamazepine-induced SJS/TEN in Han Chinese and south Asians, although a moderate association between allopurinol-induced SJS/TEN and HLA-B*5801 detected in Han Chinese was observed.
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Naoyuki KAMATANIArticle type: Review
2011 Volume 131 Issue 2 Pages 263-268
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSSince the whole human genome sequence has become available, the methods to search for genes of diseases or drugs responses (traits) have changed dramatically. The former approach designated as “candidate gene approach” is now dominated by “genome-wide approach”. In the former approach, researchers search for the genes based on the functions using biochemistry and molecular biology; however, in the latter approach, the genes are searched for by the genetic and statistical methods. Initially, monogenic diseases were the targets of the researches; however, polygenic diseases and drug responses have become the targets. Parametric linkage analysis was quite useful for identifying responsible genes for monogenic diseases. Genome-wide association study (GWAS) has been introduced for the identification of the genes for polygenic diseases and drug responses. GWAS was first introduced from 2002 to 2004 in Center for Genomic Medicine, RIKEN but has expanded rapidly to other countries including US, Europe and Asian countries from 2005. In Nature Genetics journal, about half of the articles published recently include the data from GWAS studies. Both qualitative and quantitative traits have been analyzed by GWAS. Qualitative traits include diseases and drug responses and quantitative traits include physical measures and clinical laboratory test values. Recent reports about the association between drug responses and genes have clarified many important pharmacogenomic associations. For these data to be analyzed efficiently and used appropriately; however, guidelines for researches and clinical tests concerning pharmacogenomics (PGx) are necessary. “Guideline for pharmacogenomic test” was issued in 2009 and, in addition, an extended guideline covering various fields is now being discussed.
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Reviews
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Hiroyuki AKITAArticle type: Review
2011 Volume 131 Issue 2 Pages 269-284
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSThis review summarizes the chemoenzymatic synthesis of the biologically active natural products based on a combination of chemical diastereoselectivity and enzymatic enantioselectivity using biocatalyst. Asymmetric reduction of 2-methyl-3-keto ester with yeast gave the optically active syn-2-methyl-3-hydroxy ester, which was converted to natural product such as (−)-oudemansin B. Asymmetric hydrolysis of 3-acetoxy-2-methy esters possessing syn- or anti-structure afforded the optically active 3-hydroxy-2-methyl esters and 3-acetoxy-2-methy esters corresponding to the starting material. One of these optically active 3-hydroxy-2-methyl esters was converted to aglycone of macrolide, venturicidins A and B possessing 10 chiral centers. Both primary alcohols possessing a chiral center at β-position of hydroxyl group and secondary alcohols were subjected to the lipase-assisted acylation in the presence of acyl donor to afford the optically active esters and the optically active alcohols corresponding to the starting material. These optically active compounds were converted to the biologically active natural products such as bisabolane type sesquiterpenes, decaline type diterpenes or triterpenes, nikkomycin B, (+)-asperlin, (−)-chuangxinmycin, (−)-indolmycin, cystothiazoles melithiazols, myxothiazols and piericidins possessing antifungal and cytotoxicic activities, inhibition of NADH oxidation, etc. Reaction of primary alcohol and glucose using immobilized β-glucosidase gave alkyl β-glucosides in high yield. Pentaacetate of allyl β-glucoside was subjected to Mizoroki-Heck type reaction with phenylboronic acid derivatives to give phenylpropenoid β-D-glucopyranosid congeners.
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Akira MATSUDAArticle type: Review
2011 Volume 131 Issue 2 Pages 285-298
Published: 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSChemical modification of therapeutic oligodeoxyribonucleotides (ODNs) is necessary to avoid not only degradation by endo- and exo-nucleases but also recognition by sensors such as an innate immune system. We have been developing modified nucleosides having an aminoalky linker at the pyrimidine nucleobase or sugar moiety. ODNs containing 5-N-(6-aminohexyl)carbamoyl-2′-deoxyuridine (7) were thermally stabilized about 3°C per modification and were about 160 times more stable to hydrolysis by snake venom phosphodiesterase (a 3′-exonuclease) than unmodified ODNs, but not by endonucleases. On the other hand, ODNs containing 4′-C-(aminoethyl)thymidine (14b), which was synthesized by a newly developed radical cyclization-ring-enlargement reaction by us, were 87 times more stable to hydrolysis by DNase I (an endonuclease) and 133 times more stable in 50% human serum than unmodified ODNs. The highly stereoselective synthesis of 4′-thioribonuclesides (SNs) was also developed using a Pummerer reaction. Human thrombin RNA aptamer (CII-1-37) containing 4′-thiouridine and 4′-thiocytidine was obtained by SELEX with a Kd value of 4.7 nM, while a previously known RNA aptamer (RNA-24) has a Kd value of 85 nM. Studies of the modification pattern-RNAi activity relationships by using SNs have been carried out against luciferase genes. We found that siRNAs, which have 4 residues of SNs on both ends of the sense strand and 4 residues on the 3′-end of the antisense strand, were the most effective. 4′-ThioRNA is about 1100 times more stable in 50% human plasma than unmodified RNA. However, oligoribonucleotides (SMONs) containing 2′-O-methyl-4′-thioribonucleosides were 9800 times more stable in 50% human plasma than unmodified RNA. Since SMON duplexes were thermally more stable than unmodified ON duplexes, therefore they would be quite suitable to use for oligonucleotide therapeutics.
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Ichiro TAKASAKIArticle type: Review
2011 Volume 131 Issue 2 Pages 299-306
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSHerpes zoster characterized by clustered vesicles and severe pain is caused by reactivation of varicella-zoster virus in the sensory ganglion in humans. In some herpes zoster patients, pain persists long after healing of the skin lesions, which is postherpetic neuralgia. Patients with postherpetic neuralgia report various types of pain. In addition, a large proportion describes “allodynia”, which is a painful sensation elicited by normally innocuous light mechanical stimulation. Once established, postherpetic neuralgia is particularly difficult to treat, and is often resistant to conventional analgesics. The mechanisms that underlie the induction and maintenance of herpetic pain and postherpetic neuralgia remain unclear. Therefore we attempted to establish animal models of herpetic pain and postherpetic neuralgia. This review summarizes our findings regarding the development of mouse models of herpetic pain and postherpetic neuralgia, pharmacological characterization of mouse models, mechanisms of allodynia and risk factors for postherpetic neuralgia.
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Regular Article
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Toshinobu SEKI, Nanako FUKUSHI, Hiroto MARU, Soichiro KIMURA, Sumio CH ...Article type: Regular Article
2011 Volume 131 Issue 2 Pages 307-314
Published: February 01, 2011
Released on J-STAGE: February 01, 2011
JOURNAL FREE ACCESSSperminated pullulans (SP) having different molecular weights (MWs) were prepared, and the enhancing effect on the pulmonary absorption of insulin in rats was examined. SP acted as enhancers of insulin absorption when a 0.1% solution was applied with insulin simultaneously and their enhancing effects depended on the MW of the SP; the same solutions exhibited low toxicity in the in vivo LDH leaching test. In the in vitro experiments using Calu-3 cells, tight junction-opening effects and a toxic effect of SP in the MTT assay were observed at lower concentrations compared with the in vivo experiments. A mucus layer might interfere with the interaction between SP and the cell surface and might suppress both these effects and toxicity. SP having a high MW will be useful for preparing safe and efficient formulations of peptide and protein drugs. The change in the localization of the tight junction proteins may be related to the permeation-enhancing mechanism of SP.
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