YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
134 巻, 6 号
選択された号の論文の14件中1~14を表示しています
誌上シンポジウム
  • 河原 遼, 比留間 航
    2014 年 134 巻 6 号 p. 687-688
    発行日: 2014年
    公開日: 2014/06/01
    ジャーナル フリー
  • 小堀 宅郎, 原田 慎一, 中本 賀寿夫, 徳山 尚吾
    2014 年 134 巻 6 号 p. 689-699
    発行日: 2014/06/01
    公開日: 2014/06/01
    ジャーナル フリー
      Currently, the World Health Organization recommends oral administration of opioid analgesics for patients with cancer to treat cancer-related pain from the initial stage of treatment. Furthermore, many anticancer drugs have been newly-developed and approved as oral form. Because of this trend, the chances of drug-drug interactions between anticancer drugs and opioid analgesics during absorption process from the intestine are likely to increase. To investigate these possible drug-drug interactions, we have focused on intestinal P-glycoprotein (P-gp) which regulates the absorption of various substrate drugs administered orally. Previously, we have found that repeated oral treatment with etoposide (ETP), an anticancer drug, attenuates analgesia of oral morphine, a substrate drug for P-gp, by increasing the expression and activity of intestinal P-gp. However, the mechanism by which ETP treatment increases the intestinal P-gp expression and decreases oral morphine analgesia remains unclear. RhoA, a small G-protein, and ROCK, an effector of RhoA, pathway has been attracted attention with regard to their involvement in the regulatory mechanism of the expression and activity of P-gp. Interestingly, this pathway is activated in response to various signaling induced by some anticancer drugs. Furthermore, it has been reported that ezrin/radixin/moesin (ERM) play a key role in the plasma membrane localization of P-gp, and that RhoA/ROCK pathway regulates the activation process of ERM. This review article introduces the result of our previous research as well as recent findings on the involvement of ERM via activation of RhoA/ROCK in the increased expression of intestinal P-gp and decreased oral morphine analgesia induced by repeated oral treatment with ETP.
  • 大熊 佑, 伊達 勲, 西堀 正洋
    2014 年 134 巻 6 号 p. 701-705
    発行日: 2014/06/01
    公開日: 2014/06/01
    ジャーナル フリー
      Traumatic brain injury (TBI) is one of the major causes of death and aftereffects in young individuals worldwide; however, efficient therapies for TBI are lacking at present. High mobility group box-1 (HMGB-1), which is recognized as a representative of danger-associated molecular patterns (DAMPs), plays an important role in triggering inflammatory responses in many types of diseases. We presented the involvement of HMGB-1 in TBI and evaluated the ability of intravenously administered neutralizing anti-HMGB-1 monoclonal antibody (mAb) to attenuate brain injury. Anti-HMGB-1 mAb may provide a novel and effective therapy for TBI by protecting against blood brain barrier disruption and reducing the inflammatory responses induced by HMGB-1.
  • 平野 光河, 田頭 秀章, 福永 浩司
    2014 年 134 巻 6 号 p. 707-713
    発行日: 2014年
    公開日: 2014/06/01
    ジャーナル フリー
      We previously reported that the sigma-1 receptor is down-regulated in cardiomyocytes following heart failure in transverse aortic constriction (TAC) mice. In this review, we summarized the anti-hypertrophic action of selective sigma-1 receptor agonist, SA4503 in the hypertrophied cultured cardiomyocytes and discussed its possible mechanism of cardioprotection. Treatment with SA4503 (0.1-1 μM) dose-dependently inhibited hypertrophy in cultured cardiomyocytes induced by angiotensin II (Ang II). We also found that α1 receptor stimulation by phenylephrine (PE) promotes ATP production through IP3 receptor-mediated Ca2+ mobilization into mitochondria in cultured cardiomyocytes. Interestingly, the PE-induced ATP production was impaired after Ang II-induced hypertrophy and SA4503 treatment largely restored PE-induced ATP production. The impaired PE-induced ATP production was associated with reduced mitochondrial size. The SA4503 treatment completely restored mitochondrial size concomitant with restored ATP production. These effects were blocked by sigma-1 receptor antagonist, NE-100 and sigma-1 receptor siRNA. We also confirmed that chronic SA4503 administration also significantly attenuates myocardial hypertrophy and restores ATP production in transverse aortic constriction mice. Taken together, sigma-1 receptor stimulation with selective agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca2+ mobilization and ATP production via sigma-1 receptor stimulation. Sigma-1 receptor stimulation represents a new therapeutic strategy to rescue heart from hypertrophic dysfunction in heart failure.
  • 今西 正樹, 石澤 啓介, 櫻田 巧, 石澤 有紀, 山野 範子, 木平 孝高, 池田 康将, 土屋 浩一郎, 玉置 俊晃
    2014 年 134 巻 6 号 p. 715-719
    発行日: 2014年
    公開日: 2014/06/01
    ジャーナル フリー
      Oxidative stress is a key factor involved in the pathogenesis and progression of cardiovascular disease (CVD) and chronic kidney disease (CKD). Reactive oxygen species (ROS), produced as a result of redox reactions in various cells, have been recognized as key chemical mediators causing cellular damage and organ dysfunction in CVD and CKD. Nifedipine, a well-known calcium channel blocker, is extremely sensitive to light which gets converted to its nitroso analog, nitrosonifedipine (NO-NIF) in the presence of ultraviolet and visible light. The so formed NO-NIF blocks calcium channel quite weakly compared to that of nifedipine. However, we elucidated for the first time that NO-NIF is converted to NO-NIF radical which acquires extremely strong antioxidant property via reaction with unsaturated fatty acid or endothelial cells. We have already reported that NO-NIF reduces the cytotoxicity of cumene hydroperoxide, which hampers the integrity of cell membrane through oxidative stress, in endothelial cells. Additionally, we demonstrated that NO-NIF restored acetylcholine-responsive vascular relaxation and suppressed intercellular adhesion molecule-1 expression in the aorta of Nω-nitro-L-arginine methyl ester-treated rats, a model of vascular endothelial dysfunction. Recently, we reported that NO-NIF ameliorates angiotensin II-induced vascular remodeling via antioxidative effects in vivo and in vitro. These observations point towards the plausible, unique role of NO-NIF as a novel antioxidant which improves vascular dysfunction for overcoming CVD and CKD and the same has been highlighted in this review.
  • 吉岡 靖雄, 堤 康央
    2014 年 134 巻 6 号 p. 721-722
    発行日: 2014/06/01
    公開日: 2014/06/01
    ジャーナル フリー
  • 宮山 貴光, 荒井 裕太, 鈴木 紀行, 平野 靖史郎
    2014 年 134 巻 6 号 p. 723-729
    発行日: 2014年
    公開日: 2014/06/01
    ジャーナル フリー
      Silver nanoparticles (AgNPs) are commercially used mainly as antibacterial reagents in wound dressing and deodorant powders. However, the mechanisms underlying Ag toxicity in mammals are not fully understood. In the present study, we assessed cellular distribution and toxicity of AgNPs and AgNO3 in mouse macrophage cell line (J774.1) and those of AgNO3 in human bronchial epithelial cell line (BEAS-2B) focusing on behavior of metallothionein (MT). J774.1 cells were exposed to 0-100 μg Ag/mL AgNPs or AgNO3 and BEAS-2B cells were exposed to 0-100 μM AgNO3 for 24 h. The cytotoxicity was assayed by a modified MTT method. The cellular concentration and distribution of Ag were evaluated by inductively coupled plasma-mass spectorometry (ICP-MS) and laser scanning microscopy. Distribution of Ag to MT and other proteins was determined using HPLC-ICP-MS. Most AgNPs were found in lysosomes in J774.1 at 3 h after post exposure. Ag was distributed to high molecular weight proteins in AgNPs-exposed cells, while most Ag was bound to MT in AgNO3-exposed cells. In AgNO3-exposed BEAS-2B cells cellular Ag concentration and Ag-bound MT (Ag-MT) were sharply increased up to 3 h and then decreased. ROS production appeared to cause relocation of MT-bound Ag to mitochondria, which evoked inhibition of electron transport chain. AgNPs were sequestered by high-molecular weight proteins rather than MT, probably because they were taken up by lysosomes before induction of MT.
  • 伊佐間 和郎
    2014 年 134 巻 6 号 p. 731-735
    発行日: 2014年
    公開日: 2014/06/01
    ジャーナル フリー
      Although nanomaterials are already being used for various applications in the industry, the safety of nanomaterials has not yet been sufficiently elucidated. An in vitro cellular toxicological study using well-characterized nanomaterials is conducted for the evaluation of the biological effects of nanomaterials. In this study, the effects of copper oxide nanoparticles on the global gene expression of human lung epithelial A549 cells were analyzed, and the molecular responses of A549 cells to the toxicity of the copper oxide (CuO) nanoparticles were inferred. Furthermore, the cytotoxic effects of silicon dioxide (SiO2) nanoparticles and titanium dioxide (TiO2) nanoparticles coexisting with some metal salts in Chinese hamster lung fibroblast V79 cells were also examined, and SiO2 nanoparticles increased the cytotoxicity of some of the coexisting metal salts as a result. Finally, the importance of in vitro studies in the safety evaluation of nanomaterials was discussed.
  • 吉岡 靖雄, 堤 康央
    2014 年 134 巻 6 号 p. 737-742
    発行日: 2014/06/01
    公開日: 2014/06/01
    ジャーナル フリー
      Recently, it is concerned that nanomaterials induce undesirable biological responses (NanoTox) which is different from conventional materials attributed to their unique physicochemical properties in the world. However, for our enjoying the benefits of nanomateirals, it is most important not to regulate nanomaterials in the blind way but to assure the security of nanomaterials and support the development of nanomaterial industries. These are duty of our country to be advanced country, technology-oriented nation and intellectual property nation. From these viewpoints, we are engaged on not NanoTox study but Nano-safety science study. In this review, we will introduce our Nano-safety science study using mainly silica nanoparticle.
総説
  • 小島 周二
    2014 年 134 巻 6 号 p. 743-749
    発行日: 2014/06/01
    公開日: 2014/06/01
    ジャーナル フリー
      We previously reported that low doses (0.25-0.5 Gy) of γ-rays induce intracellular antioxidant, radioresistant, DNA damage repair, and so on. Meanwhile, we have recently reported that ATP is released from the cells exposed to low-dose γ-rays. Here, it was investigated whether or not γ-radiation-induced release of extracellular ATP contributes to various radiation effects, in paricular, focusing on the inductions of intracellular antioxidant and DNA damage repair. Irradiation with γ-rays or exogenously added ATP increased expression of intracellular antioxidants such as thioredoxin and the increases were blocked by pretreatment with an ecto-nucleotidase in both cases. Moreover, release of ATP and autocrine/paracrine positive feedback through P2Y receptors serve to amplify the cellular repair response to radiation-induced DNA damage. To sum up, it would be suggested that ATP signaling is important for the effective induction of radiation stress response, such as protection of the body from the radiation and DNA damage repair. In addition, the possibility that this signaling is involved in the radiation resistance of cancer cells and beneficial effect on the organism of low-dose radiation and radiation adaptive response, would be further suggested.
ノート
  • 佐藤 淳也, 森 恵, 佐々木 拓弥, 二瓶 哲, 熊谷 真澄, 中山 誠也, 高橋 勝雄, 工藤 賢三
    2014 年 134 巻 6 号 p. 751-756
    発行日: 2014年
    公開日: 2014/06/01
    ジャーナル フリー
      For medical professionals involved in cancer chemotherapy, occupational exposure of anticancer agents is considered a health risk. Education about the handling of anticancer drugs and proper use of protective equipment are important for reducing occupational exposure of anticancer drugs. Furthermore, monitoring of the contamination level of anticancer drugs is important for determining the propriety of anti-contamination methods. Cyclophosphamide (CPA) has been used as the standard drug of the contamination level; however, it is rarely detected because of the disparity between drug preparation frequency and consumption, and use of a closed system. Therefore, we chose 5-fluorouracil (5-FU) as the standard drug and attempted to monitor its contamination levels by sampling using drug absorption sheets (the coupon method). We measured contamination levels inside a biological safety cabinet (BSC) and at its lower floor, and at a preparation worktable, nurses' station worktable, its lower floor and floor of the hospital room in a chemotherapy room for outpatients of the Iwate Medical University Hospital for 3 time periods. 5-FU was detected in 72% of the coupons (n=108), while CPA was detected in only 7% of the coupons (n=108). Monitoring of 5-FU contamination levels by using the coupon method was considered useful for evaluating anti-contamination method and the contamination process.
  • 田中 真吾, 朝比奈 泰子, 佐藤 宏樹, 三木 晶子, 堀 里子, 澤田 康文
    2014 年 134 巻 6 号 p. 757-766
    発行日: 2014/06/01
    公開日: 2014/06/01
    ジャーナル フリー
      It has been reported the use of nonsteroid anti-inflammatory drugs (NSAIDs) in late pregnancy was associated with potentially fetal toxicity (contraction of fetal ductus areteriosus). According to the package inserts in Japan, many oral NSAIDs are contraindicated to women in late pregnancy, but several oral and topical NSAIDs with case reports of fetal toxicity are not. In the present study, a web-based questionnaire survey was conducted in pharmacists/physicians to determine their awareness of fetal toxicity caused by NSAIDs, as well as their attitudes regarding the use of NSAIDs in late pregnancy. Responses were obtained from 427 pharmacists, 22 obstetricians, and 160 non-obstetric physicians. Of the non-obstetric respondents, more than 40% had no knowledge of fetal ductus arteriosus contraction caused by oral ibuprofen, and most of them were not aware of the relevant warning statement on the package insert. In contrast, these were familiar to nearly 100% of the obstetricians. As for ketoprofen tape, only 20-40% of the pharmacists/physicians were aware of the warning statement, and nearly all respondents did not confirm whether the patient was in late pregnancy. The majority of the respondents answered that oral ibuprofen, ketoprofen tape and NSAID-containing OTC drugs should not be used in late pregnancy after they knew the warning statements in late pregnancy. This survey suggests that the fetal toxicity of NSAIDs is not well recognized by pharmacists/physicians. It would be necessary to make it thoroughly known to them through such as enrichment of safety information on the package inserts, accompanying with the evidence.
  • 高橋 竜也, 寺町 ひとみ, 舘 知也, 野口 義紘, 長澤 宏之, 水井 貴詞, 後藤 千寿, 土屋 照雄
    2014 年 134 巻 6 号 p. 767-774
    発行日: 2014/06/01
    公開日: 2014/06/01
    ジャーナル フリー
      The combination of angiotensin receptor blockers (ARB) and a thiazide diuretic (hereafter, ARB/diuretic) is expected to improve patient adherence and increase the therapeutic effects because of the lower number of pills that require to be administered. In addition, an ARB/diuretic combination alleviates hypokalemia that frequently develops in patients receiving thiazide diuretics. In this study, we used electronic medical records to investigate the laboratory values (serum levels of potassium, sodium, and uric acid) of 194 ambulatory and hospitalized patients at the Gifu Municipal Hospital who received ARB/diuretic combination therapy for the first time between February 2010 and September 2012. According to the grade of classification of low serum potassium and sodium levels, the serum potassium level in one patient was grade 3 and the serum sodium level in two patients was grade 3 after the initiation of ARB/diuretic combination therapy. After administration of ARB/diuretic combination therapy, two patients received potassium supplements because their serum potassium levels decreased below the reference value. Similarly, one patient received a sodium supplement because of a decrease in the sodium level below the reference value. Uric acid level increased above the reference value after administration of the ARB/diuretic combination therapy in one patient; thus, this patient received antihyperuricemic agents. Therefore, pharmacists must carefully monitor the serum levels of potassium, sodium, and uric acid, particularly in the first six months after the initiation of ARB/diuretic combination therapy.
  • 岩﨑 綾乃, 辻 明弘, 今井 公江, 中西 邦夫
    2014 年 134 巻 6 号 p. 775-780
    発行日: 2014/06/01
    公開日: 2014/06/01
    ジャーナル フリー
      There is little information regarding the acid-neutralizing capacity of over-the-counter (OTC) gastrointestinal medicines. In this study, we assessed the acid-neutralizing capacity of OTC and prescribed gastrointestinal drugs based on the Japanese Pharmacopoeia 16th Edition. The acid-neutralizing capacity of the OTC drugs was calculated using experimental results for the crude materials found in the prescribed drugs based on OTC antacid quantity. The measured acid-neutralizing capacities of the OTC drugs agreed with the respective calculated values. These results indicate that the acid-neutralizing capacity of OTC drugs labeled as an antacid without information on their capacity can be estimated based on the quantity and capacity of the antacid components.
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