日本薬理学雑誌
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
106 巻, 3 号
選択された号の論文の8件中1~8を表示しています
  • 創薬科学-分子から個体への薬理学
    松野 浩之, Marc F. HOYLAERTS, Jos VERMYLEN, Hans DECKMYN
    1995 年 106 巻 3 号 p. 143-155
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Activation of platelets leads to thrombosis and secretion of PDGF and other stimulators of smooth muscle cell (SMC) migration/proliferation, resulting in neointima formation. RGD-containing peptides can prevent the binding of several integrins including αIIb/β3 (GP II b/ III a) in platelet aggregation and αv/β3 in smooth muscle cell migration, both of which are involved in neointima formation. Thrombus formation was measured by transillumination and image analysis at 30 min, 24 hr and 72 hr after vascular injury and neointima was quantified in the same carotid arteries in hamsters at 2 weeks. The proliferation index of SMC was determined at 1, 3, 5, 7, and 14 days after denudation following four injections of BrdU. After treatment with G4120 at a dose of 100 μg/kg/hr, both thrombus size (89.2 ± 5.5% inhibition vs control) and neointima formation (60.2 ± 6.6% inhibition vs control) were significantlly reduced. Pooling individual data for treated hamsters with those obtained for the untreated animals still resulted in a significant correlation (r=0.64, n=47, P < 0.001). Reduction of neointima by G4120 is linked to a lower percentage of proliferating cells in the media and neointima from 16.5 ± 9.7% on day 1 (media) and 20.2 ± 7.3% on day 5 (intima) in the control animals to 9.9 ± 6.1% on day 1 (media) and 13.4 ± 9.0 on day 5 (intima) in the G4120 treated animals. In conclusion, inhibition of integrin function results in reductions of thrombus and neointima formations. This effect is due both an early event, which is caused by inhibition of PDGF secretion by platelets with blocked α Ilb/β3, and to a late event, possibly by interference with SMC αv/β3.
  • 創薬科学-分子から個体への薬理学
    柳澤 輝行
    1995 年 106 巻 3 号 p. 157-169
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Studies performed to elucidate the inhibitory mechanisms of the hyperpolarization induced by K+ channel openers on the Ca2+ movements and force of contraction produced by either the stimulation of thromboxane A2 receptors or depolarization with high KCl have shown the following: When the plasma membrane is hyperpolarized by K+ channel openers, voltage-dependent Ltype Ca2+ channels are deactivated and the influx of Ca2+ is decreased, as is the case with the KCl-induced Call influx. The hyperpolarization of the plasma membrane also has other inhibitory effects on phospholipase C, a membrane-associated enzyme activity. The IP3 production and IP3-induced Ca2+ release from intracellular stores, which is related to the stimulation of the agonist receptors, are inhibited by the hyperpolarization of the plasma membrane by K+ channel openers. Recently, we showed that the Ca2+ sensitivity of the contractile elements was voltage dependent. Furthermore, membrane hyperpolarization induced by various K+ channel openers relaxed canine coronary arteries more profoundly than decreased [Ca2+]i. Thus, the membrane voltage may regulate intracellular enzyme activities, including contractile elements. Therefore, this new facet of signal transduction should be considered in the control of vascular tone. The evolutional relationships of various K+ channels are also discussed.
  • 創薬科学-分子から個体への薬理学
    宮田 桂司, 西田 明登, 本田 一男
    1995 年 106 巻 3 号 p. 171-179
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Gastrin plays an important role in gastrointestinal functions such as gastric secretion and mucosal growth. The hypergastrinemia that results from long-term treatment with proton pump inhibitors and histamine H2-receptor antagonists induces hyperplasia of enterochromaffin-like (ECL) cells and increases the secretory response to pentagastrin (acid rebound). Recently, potent and selective gastrin/CCK-B-receptor antagonists, L-365, 260, PD 136450 and YM022, have been developed. These compounds inhibit basal and meal-stimulated acid secretion as well as pentagastrin-stimulated acid secretion in rats and dogs. Long-term treatment with gastrin/CCKB-receptor antagonists does not cause hyperplasia of ECL cells and acid rebound at all. Moreover, they prevent hyperplasia and acid rebound induced by proton pump inhibitors and histamine H2-receptor antagonists. Therefore, gastrin/CCK-B-receptor antagonists are suggested to be novel antiulcer and antisecretory agents without potential for acid rebound, hyperplasia and carcinoid.
  • 創薬科学-分子から個体への薬理学
    近藤 規元, 浜中 信行
    1995 年 106 巻 3 号 p. 181-190
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    In searching for new drugs, we have developed receptor binding assays for prostanoids. Among the various compounds that we have tested, we have found that hydronaphthalene derivatives can interact with some prostanoid receptors. Modification of such compounds produced several pure prostacyclin agonists (ONO-AP-227 and ONO-AP-437) and a unique prostacyclin agonist with inhibitory activity against thromboxane synthase (ONO-AP-500-02). These compounds showed specific binding to the IP receptor with Ki values less than 0.2 μM, without binding to EP and TP receptors. These compounds also inhibited human platelet aggregation with IC50 values of 0.03-0.24 μM. These compounds inhibited ex vivo platelet aggregation in dogs or rats in the dose range of 1 to 30 mg/kg. Furthermore, ONO-AP-500-02 inhibited ex vivo thromboxane formation at doses similar to those inhibiting platelet aggregation in rats. These results, taken together, suggest that chemical syntheses of compounds targeting prostanoid receptors can produce unique prostanoid agonists or antagonists, and rational syntheses might be possible for compounds with different pharmacological actions such as inhibition of thromboxane synthase.
  • 創薬科学-分子から個体への薬理学
    藤井 隆
    1995 年 106 巻 3 号 p. 193-203
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    In order to create a new drug for the treatment of respiratory diseases, such as asthma and chronic bronchitis, having a novel therapeutic mechanism, we have been trying to develop new compounds with neurokinin (NK)-receptor antagonistic effects. We used [3H]-substance P binding to guinea pig lung membrane for the first screening system and successfully discovered FK224 from a fermentation product and FK888 from chemical design studies using an octapeptide antagonist (D-Pro4, D-Trp7, 9, 10) SP4-11 as the parent compound. FK224 and FK888 showed different selectivities against the NK-receptor subtypes (NK1, NK2, NK3); FK888 was a highly potent NK1-selective antagonist, and FK224 was a NK1 +NK2 dual receptor antagonist. Neither compound had any activity on the NK3 receptor. In the in vivo experiments, FK224 and FK888 significantly inhibited the constriction and plasma extravasation in the airway induced by agonist injection. These compounds also showed inhibitory effects on the airway response induced by capsaicin and antidromic stimulation of vagus nerves. Furthermore, FK224 and FK888 were effective on the mucus secretion in the airway and the cough reflex induced by citric acid challenge. There were some differences in the effects of FK224 and FK888 in the in vivo experiments, and it was suggested that the NK1 receptor and NK2 receptor were mainly involved in neurogenic inflammation and airway constriction, respectively. FK224 and FK888 are now undergoing clinical studies to test the effectiveness of a NK antagonist in human respiratory diseases.
  • 創薬科学-分子から個体への薬理学
    木村 征夫
    1995 年 106 巻 3 号 p. 205-216
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    In platelets, an increase in cAMP levels potently inhibits aggregation and release reactions. Cilostazol is an antiplatelet agent that increases intracellular cAMP levels by selective Type III phosphodiesterase (PDE) inhibition. The characteristics of cilostazol are presented in this review. Adenylate cyclase potentiator also shows strong inhibitory actions on platelet functions, but a number of reports suggest that the continuous use of an adenylate cyclase potentiator may lead to a reduction of drug efficacy. On the other hand, such an action has not been seen with cilostazol even after continuous administration of cilostazol (100 mg/kg) for two weeks in rats, which may be due to a feature of this drug, namely, inhibitory actions on PDE. Inhibitory actions of cilostazol on PDE are specific: strong inhibition (IC50 = 0.19 μM) against Type III PDE that comprises most of the PDE activities in platelets and weak inhibition against Type IV PDE that comprises most of the PDE activities in endothelial cells (ECs). This fact (i.e., specificity of cilostazol) brought about important results when the drug reacted in the presence of both platelets and blood vessels. A non-specific PDE inhibitor such as IBMX increases cAMP and decreases PGI2 synthesis in ECs, but such a phenomenon was not seen with cilostazol. The inhibitory actions of cilostazol on platelet functions were potently enhanced in the presence of PGI2. This phenomenon was reproduced in vivo, i.e., antiplatelet actions of cilostazol in vivo were approximately 50 times more potent than those in vitro. Cilostazol also strongly inhibits Type III PDE in vascular smooth muscle cells (SMCs) causing inhibition of SMC proliferation in vitro and inhibition of intimal hyperplasia in vivo. Therefore, it is considered that PDE III inhibitors such as cilostazol have great additional value as an antithrombotic agent.
  • 創薬科学-分子から個体への薬理学
    桂 昌司, 大熊 誠太郎, 栗山 欣弥
    1995 年 106 巻 3 号 p. 217-227
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    This review summarizes the data showing the possible involvement of an endogenous ligand for benzodiazepine (BDZ) receptors, diazepam binding inhibitor (DBI), in the development of alcohol dependence. The expression of cerebral DBI mRNA significantly increased in EtOH-inhaled and EtOH-withdrawn mice in comparison with that in EtOH-untreated mice, whereas the DBI mRNA level was not altered after a single administration of EtOH. After EtOH-withdrawal, this increase in the DBI mRNA expression in the mouse cerebral cortex diminished over 14 days despite the disappearance of withdrawal signs within 2 days after the withdrawal of EtOH. Simultaneous administration of flunitrazepam, a BDZ receptor agonist, with EtOH completely abolished the EtOH-induced increase in DBI mRNA expression. These results lead to the assumption that the changes in the expression of cerebral DBI mRNA induced by continuous EtOH treatment may be involved in the establishment of alcohol dependence, and such changes may be also regulated by BDZ receptors.
  • 創薬科学-分子から個体への薬理学
    山田 陽城
    1995 年 106 巻 3 号 p. 229-236
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Several pharmacological activities have been observed in pectic polysaccharides which were isolated from Chinese herbs containing Kampo medicines. We found two different bioactive pectic polysaccharides, bupleuran 2IIb and 2IIc, from the roots of Bupleurum falcatum. These bioactive pectic polysaccharides were comprised of an α (1→4) linked galacturonan region, a ramified region that consists of a rhamnogalacturonan core substituted neutral sugar chains as the side chains and a rhamnogalacturonan II (RG II)-like region containing unique sugars such as 3-deoxy-manno-2-octulosonic acid (KDO). In order to understand the pharmacological activity of pectic polysaccharides on the molecular level, we have elucidated the essential carbohydrate structure for the expression of each pharmacological activity and their mode of actions. The ramified region in bupleuran 2IIb induced Fc receptor up-regulation in macrophages by a mechanism dependent on an increase of intracellular Ca2+, followed by the enhancement of immune complex clearance, whereas bupleuran 2IIc, which mainly consists of a partially branched galacturonan region, showed potent anti-ulcer activity. The major mechanism of its mucosal protection was suggested to be due to anti-secretory activity on acid and pepsin, its ability to provide a protective coating and radical scavenging effect. The future problems were also discussed in order to develop pectic polysaccharides as medicines.
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