Japanese journal of pharmacology最新文献_第7页

The nitric oxide donor NOC12 protects cultured astrocytes against apoptosis via a cGMP-dependent mechanism. 一氧化氮供体no12通过cgmp依赖机制保护培养的星形胶质细胞免于凋亡。

Japanese journal of pharmacology Pub Date : 2002-05-01 DOI: 10.1254/JJP.89.64

K. Takuma, Patamawan Phuagphong, Eibai Lee, R. Enomoto, K. Mori, A. Baba, T. Matsuda

{"title":"The nitric oxide donor NOC12 protects cultured astrocytes against apoptosis via a cGMP-dependent mechanism.","authors":"K. Takuma, Patamawan Phuagphong, Eibai Lee, R. Enomoto, K. Mori, A. Baba, T. Matsuda","doi":"10.1254/JJP.89.64","DOIUrl":"https://doi.org/10.1254/JJP.89.64","url":null,"abstract":"We examined the effect of 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC12), a nitric oxide (NO) donor, on apoptosis in cultured astrocytes. Reperfusion after hydrogen peroxide (H2O2) exposure caused a decrease in cell viability, loss of mitochondrial membrane potential, caspase-3 activation, DNA ladder formation, and nuclear condensation. NOC12 at 10-100 microM significantly attenuated these apoptotic changes, while the NO donor at 1 mM caused cell injury and exacerbated the H202-induced cell injury. NOC12 increased intracellular cGMP levels in a dose dependent manner with the maximal effect at 100 microM. The protective effect of NOC12 was mimicked by the NO-independent guanylate cyclase activator 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole, and was attenuated by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and the cGMP-dependent protein kinase inhibitor KT5823. ODQ and KT5823 did not block but rather exacerbated the cytotoxic effect of NOC12 at 1 mM. These findings demonstrate that lower concentrations of NOC12 inhibit the H2O2-induced apoptosis of astrocytes in a cGMP-dependent way, but higher concentrations of NOC12 show a toxic effect on astrocytes in a cGMP-independent way.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"11 1","pages":"64-71"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84338451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 24

Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. 新型乙酰胆碱酯酶抑制剂盐酸多奈哌齐的研制。

Japanese journal of pharmacology Pub Date : 2002-05-01 DOI: 10.1254/JJP.89.7

H. Sugimoto, H. Ogura, Y. Arai, Y. Limura, Y. Yamanishi

{"title":"Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor.","authors":"H. Sugimoto, H. Ogura, Y. Arai, Y. Limura, Y. Yamanishi","doi":"10.1254/JJP.89.7","DOIUrl":"https://doi.org/10.1254/JJP.89.7","url":null,"abstract":"A wide range of evidence shows that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyrylcholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"48 1","pages":"7-20"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89252647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 188

Cardioprotective effects of 9-hydroxyellipticine on ischemia and reperfusion in isolated rat heart. 9-羟基利匹汀对离体大鼠心脏缺血再灌注的保护作用。

Japanese journal of pharmacology Pub Date : 2002-05-01 DOI: 10.1254/JJP.89.21

K. Saeki, I. Obi, N. Ogiku, M. Shigekawa, T. Imagawa, Takeshi Matsumoto

引用次数: 6

Existence of ionotropic glutamate receptor subtypes in cultured rat retinal ganglion cells obtained by the magnetic cell sorter method and inhibitory effects of 20-hydroxyecdysone, a neurosteroid, on the glutamate response. 磁细胞分选法获得的培养大鼠视网膜神经节细胞中存在嗜离子性谷氨酸受体亚型及神经甾体20-羟基脱皮酮对谷氨酸反应的抑制作用

Japanese journal of pharmacology Pub Date : 2002-05-01 DOI: 10.1254/JJP.89.44

S. Mukai, H. Mishima, K. Shoge, Makoto Shinya, K. Ishihara, M. Sasa

{"title":"Existence of ionotropic glutamate receptor subtypes in cultured rat retinal ganglion cells obtained by the magnetic cell sorter method and inhibitory effects of 20-hydroxyecdysone, a neurosteroid, on the glutamate response.","authors":"S. Mukai, H. Mishima, K. Shoge, Makoto Shinya, K. Ishihara, M. Sasa","doi":"10.1254/JJP.89.44","DOIUrl":"https://doi.org/10.1254/JJP.89.44","url":null,"abstract":"Glutamate and neurosteroids are known to exist in retinal ganglion cells (RGC). Therefore, patch clamp studies using the whole-cell recording method were performed to determine whether or not ionotropic glutamate receptor subtypes, i.e., N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors, were present on RGC obtained by the magnetic cell sorter (MACS) method and cultures. In addition, the effects of 20-hydroxyecdysone (20-HE), a neurosteroid, on inward currents induced by NMDA, AMPA and kainate were examined at a holding potential of -60 mV. The current-voltage relationship for NMDA in the presence of glycine and Mg2+-free, as well as those for AMPA and kainate were linear, with a reversal potential of around 0 mV. NMDA-induced currents were blocked by MK-801, while both AMPA- and kainate-induced currents were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Application of 20-HE in the bath resulted in significant inhibitions on NMDA-, AMPA- and kainate-induced currents. Thus, NMDA, AMPA and kainate receptors were confirmed to exist on MACS-separated cultured RGC. Moreover, 20-HE inhibited NMDA receptor-mediated currents most prominently and AMPA- and kainate-mediated currents moderately, suggesting that neurosteroids may be playing a role in modulating glutamate-mediated transmission in RGC, and 20-HE might be useful for preventing glutamate neurotoxicity.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"154 1","pages":"44-52"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77704484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Modulation by 5-hT2A receptors of aggressive behavior in isolated mice. 5-hT2A受体对离体小鼠攻击行为的调节。

Japanese journal of pharmacology Pub Date : 2002-05-01 DOI: 10.1254/JJP.89.89

M. Sakaue, Y. Ago, C. Sowa, Y. Sakamoto, Beni Nishihara, Y. Koyama, A. Baba, T. Matsuda

引用次数: 69

Dipeptidyl peptidase IV inhibition improves impaired glucose tolerance in high-fat diet-fed rats: study using a Fischer 344 rat substrain deficient in its enzyme activity. 二肽基肽酶IV抑制改善高脂肪饮食喂养大鼠葡萄糖耐量受损:使用酶活性缺乏的Fischer 344大鼠亚株的研究

Japanese journal of pharmacology Pub Date : 2002-04-01 DOI: 10.1254/JJP.88.442

H. Mitani, M. Takimoto, T. Hughes, M. Kimura

{"title":"Dipeptidyl peptidase IV inhibition improves impaired glucose tolerance in high-fat diet-fed rats: study using a Fischer 344 rat substrain deficient in its enzyme activity.","authors":"H. Mitani, M. Takimoto, T. Hughes, M. Kimura","doi":"10.1254/JJP.88.442","DOIUrl":"https://doi.org/10.1254/JJP.88.442","url":null,"abstract":"This study was performed to determine the effects of a high-fat diet on glucose metabolism after an oral glucose challenge in high-fat diet-fed dipeptidyl peptidase IV (DPP-IV) positive (+) and deficient (-) Fischer 344 (F344) rats and the effects of novel DPP-IV inhibitor NVP-DPP728 (1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine monohydrochloride salt) on glucose tolerance in high-fat diet-fed F344 rats. In DPP-IV(+) rats, a high-fat diet load caused impaired glucose tolerance, such as increases of plasma insulin and blood glucose concentrations after oral glucose challenge, compared with a standard chow-fed group. In contrast, no marked change in glucose tolerance was induced by the high-fat diet in DPP-IV(-) rats. Blood glucose concentrations in DPP-IV(-) rats after glucose challenge were significantly lower than in DPP-IV(+) rats under high-fat diet load conditions. In standard chow and high-fat diet-fed DPP-IV(+) rats, NVP-DPP728 significantly suppressed glucose excursions after glucose challenge by inhibiting the plasma DPP-IV activity, associated with the stimulation of early insulin secretion. NVP-DPP728 did not affect glucose tolerance in DPP-IV(-) rats under both conditions. These results indicate that the amelioration of glucose tolerance by NVP-DPP728 in DPP-IV(+) rats was directly due to the inhibition of plasma DPP-IV activity, which might be via the subsequent increase in endogenous incretin action.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"32 1","pages":"442-50"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89681973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 61

Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug. 新型抗过敏药物盐酸奥洛他定的药理、药动学及临床性质。

Japanese journal of pharmacology Pub Date : 2002-04-01 DOI: 10.1254/JJP.88.379

K. Ohmori, K. Hayashi, T. Kaise, E. Ohshima, Satoshi Kobayashi, T. Yamazaki, A. Mukouyama

{"title":"Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug.","authors":"K. Ohmori, K. Hayashi, T. Kaise, E. Ohshima, Satoshi Kobayashi, T. Yamazaki, A. Mukouyama","doi":"10.1254/JJP.88.379","DOIUrl":"https://doi.org/10.1254/JJP.88.379","url":null,"abstract":"Olopatadine hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002).","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"47 1","pages":"379-97"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80856437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 93

Dipeptidyl peptidase IV inhibitor NVP-DPP728 ameliorates early insulin response and glucose tolerance in aged rats but not in aged Fischer 344 rats lacking its enzyme activity. 二肽基肽酶IV抑制剂NVP-DPP728改善老年大鼠的早期胰岛素反应和葡萄糖耐量，但对缺乏其酶活性的老年Fischer 344大鼠无效。

Japanese journal of pharmacology Pub Date : 2002-04-01 DOI: 10.1254/JJP.88.451

H. Mitani, M. Takimoto, M. Kimura

{"title":"Dipeptidyl peptidase IV inhibitor NVP-DPP728 ameliorates early insulin response and glucose tolerance in aged rats but not in aged Fischer 344 rats lacking its enzyme activity.","authors":"H. Mitani, M. Takimoto, M. Kimura","doi":"10.1254/JJP.88.451","DOIUrl":"https://doi.org/10.1254/JJP.88.451","url":null,"abstract":"The aim of this study was to investigate the effects of aging on glucose metabolism after oral glucose challenge in aged dipeptidyl peptidase IV (DPP-IV) positive (+) Fischer 344 (F344), DPP-IV deficient (-) F344 and DPP-IV(+) Wistar rats and to determine the effect of a DPP-IV inhibitor NVP-DPP728 (1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine monohydrochloride salt) on glucose tolerance in aged rats. Aging caused a decrease in early insulin response after an oral glucose challenge in aged Wistar or DPP-IV(+) F344 rats, but not in aged DPP-IV(-) F344 rats, compared with young control groups. Glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats was better than in aged DPP-IV(+) F344 and Wistar rats associated with the preservation of the early insulin response. NVP-DPP728 improved the glucose tolerance after an oral glucose challenge by potentiating the early insulin response throughout the inhibition of plasma DPP-IV activity in aged DPP-IV(+) Wistar and F344 rats. In contrast, NVP-DPP728 did not affect the glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats. These results indicate that treatment with NVP-DPP728 ameliorated glucose tolerance in aged rats by the direct inhibition of plasma DPP-IV activity and presumably the subsequent increase in endogenous incretin action.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"26 1","pages":"451-8"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82625097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 32

Involvement of glutamate receptors within the central nucleus of the amygdala in naloxone-precipitated morphine withdrawal-induced conditioned place aversion in rats. 杏仁核中央核谷氨酸受体参与纳洛酮沉淀吗啡戒断诱导的大鼠条件厌恶。

Japanese journal of pharmacology Pub Date : 2002-04-01 DOI: 10.1254/JJP.88.399

Takeshi Watanabe, T. Nakagawa, R. Yamamoto, Akifumi Maeda, M. Minami, M. Satoh

{"title":"Involvement of glutamate receptors within the central nucleus of the amygdala in naloxone-precipitated morphine withdrawal-induced conditioned place aversion in rats.","authors":"Takeshi Watanabe, T. Nakagawa, R. Yamamoto, Akifumi Maeda, M. Minami, M. Satoh","doi":"10.1254/JJP.88.399","DOIUrl":"https://doi.org/10.1254/JJP.88.399","url":null,"abstract":"Chronic use of morphine leads to physical and psychological dependence. The amygdala is known to be involved in the expression of emotion such as anxiety and fear, and several studies have shown that the central nucleus of the amygdala (CeA) is involved in morphine dependence. In the present study, we investigated the role of glutamate receptors within the CeA in the negative affective component of morphine abstinence by evaluating naloxone-precipitated withdrawal-induced conditioned place aversion (CPA) in morphine-dependent rats. We found that microinjection of the AMPA/kainate-glutamate-receptor antagonist CNQX (30 nmol/side) into the bilateral CeA significantly attenuated the naloxone-precipitated withdrawal-induced CPA, as well as several somatic signs, in morphine-dependent rats, without preference or aversive effects by itself in non-dependent rats. Furthermore, microinjection of the non-competitive NMDA-receptor antagonist MK-801 (30 nmol/side) or competitive NMDA-receptor antagonist D-CPPene (0.01 and 0.1 nmol/side) into the CeA significantly attenuated the naloxone-precipitated morphine withdrawal-induced CPA, but not somatic withdrawal signs. These results suggest that the activation of AMPA /kainate and NMDA receptors within the CeA play a crucial role in the negative affective component of morphine abstinence.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"23 1","pages":"399-406"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77491757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 96

Effects of a Typical IKr Channel Blocker Sematilide on the Relationship Between Ventricular Repolarization, Refractoriness and Onset of Torsades de Pointes 一种典型的IKr通道阻滞剂Sematilide对心室复极、耐火度和点扭转发病关系的影响

Japanese journal of pharmacology Pub Date : 2002-04-01 DOI: 10.1254/JJP.88.414

A. Sugiyama, K. Hashimoto

{"title":"Effects of a Typical IKr Channel Blocker Sematilide on the Relationship Between Ventricular Repolarization, Refractoriness and Onset of Torsades de Pointes","authors":"A. Sugiyama, K. Hashimoto","doi":"10.1254/JJP.88.414","DOIUrl":"https://doi.org/10.1254/JJP.88.414","url":null,"abstract":"The effects of a typical IKr channel blocker sematilide on the relationship between ventricular repolarization, refractoriness and onset of torsades de pointes (TdP) were studied using the canine isolated, blood-perfused ventricular septum preparation with monophasic action potential (MAP) recording. Intra-coronary infusion of sematilide (10 – 100 μg/min) prolonged the repolarization phase and effective refractory period, the extent of which was greater in the former than in the latter, resulting in prolongation of terminal repolarization process. Prolonging the basic pacing cycle length from 400 to 600 ms and/or increasing the drug doses enhanced each of these actions. Reverse use-dependence was obvious in the drug-induced prolongation of MAP duration, but it was less clear in the effective refractory period. More importantly, during sematilide infusion, in preparations paced at longer basic cycle length of 600 – 2000 ms, TdP-like polymorphic ventricular tachycardia was repeatedly induced by an extra-stimulus applied on the terminal repolarization phase, which indicates the appearance of electrically vulnerable period. Prolonging the basic pacing cycle length and/or increasing the drug doses prolonged this electrically vulnerable period in parallel with the terminal repolarization phase. These results suggest that prolongation of the terminal repolarization process by sematilide would enhance the chance of conduction slowing at less complete repolarization levels, which may be associated with a high incidence of TdP induction.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"38 1","pages":"414-421"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84059363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 43