Development of new drugs for the treatment of congestive heart failure
治疗充血性心力衰竭新药的开发
基本信息
- 批准号:07557193
- 负责人:
- 金额:$ 1.41万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (A)
- 财政年份:1995
- 资助国家:日本
- 起止时间:1995 至 1997
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The congestive heart failure (CHF) affects approximately 10 million adults worldwide and is the most common reason for hospital admission in patients over the age of 65. The incidence of mortality is high. Between 10-50% of patients with the CHF die annually. The therapy of the disease has not yet been settled and the concept for the treatment is shifting between two notions. The purpose of the treatment is twofold : 1) unloading to the cardiac pump ; 2) increase in myocardial contractility. Although the drugs that act by the latter mechanism have been shown to improve the quality of life (QOL) of the patients by improving the hemodynamic parameters and the exercise capacity, the long-term treatment with these agents has failed to show a beneficial effect on the survival of the patients but even shortened the life-span of the patients with CHF compared with placebo. Thus the focus of the treatment has currently been shifted more to the former. It has to be noted, however, that all of t … More he existing positive inotropic agents, such as digitalis, catecholamines and PDEIII inhibitors act through an increase in intracellular Ca^<2+> mobilization : combined application of these agents could readily result in Ca^<2+> overload in myocardial cells that leads to various types of arrhythmias, an increase in myocardial oxygen consumption, myocardial cell injury and death. In addition under pathological condition after myocardial ischemia such as stunned myocardium, these cardiotonic agents lose their effectiveness to increase myocardial contractility. Since Ca^<2+> sensitizers overcome these drawbacks of pre-existing agents, they have high potential for the treatment of CHF.In this study it is clearly shown that a Ca^<2+> sensitizer Org 30029 elicits a positive inotropic effect even under acidosis or in the presence of butanedione monoxime (BDM). Furthermore the mechanism of actions of newer Ca^<2+> sensitizers, including levosimendan, SCHOOO13 and MCI-154 has been elucidated ; all of these agents act through a dual mechanism, Ca^<2+> sensitization and PDEIII inhibition, in the basic study in animal models. Clinical studies with the first and third compounds have been launched. The second agent is unique in that even in animal models it has no chronotropic action, which could be an important property of cardiotonic agents. Novel effective therapeutic agents for application in the patients with CHF could be developed from the family of compounds that increase myofibrillar Ca^<2+> sensitivity. Less
充血性心力衰竭(CHF)影响全球约1000万成年人,是65岁以上患者入院的最常见原因。死亡率很高。每年有10-50%的CHF患者死亡。该疾病的治疗尚未解决,治疗的概念正在两个概念之间转变。治疗的目的有两个:1)卸载到心脏泵; 2)增加心肌收缩力。尽管通过后一种机制起作用的药物已被证明通过改善血流动力学参数和运动能力来改善患者的生活质量(QOL),但与安慰剂相比,用这些药物进行的长期治疗未能显示对患者生存的有益作用,甚至缩短了CHF患者的寿命。因此,治疗的重点目前已更多地转移到前者。但必须指出的是,所有T ...更多信息 现有的正性肌力药物,如洋地黄、儿茶酚胺和PDEIII抑制剂通过增加细胞内Ca^2+动员而起作用:这些药物的联合应用容易导致心肌细胞中Ca^2+过载,从而导致各种类型的心律失常、心肌耗氧量增加、心肌细胞损伤和死亡。此外,在心肌缺血后的病理状态下,例如心肌顿抑,这些强心剂失去了增加心肌收缩力的效果。由于Ca^2+增敏剂克服了现有药物的这些缺点,因此它们在治疗CHF方面具有很高的潜力。本研究清楚地表明,Ca^2+增敏剂P30029即使在酸中毒或丁二酮单肟(BDM)存在下也能发挥正性肌力作用。此外,包括左西孟旦、SCHOOO 13和MCI-154在内的新型Ca^2+增敏剂的作用机制也已阐明;在动物模型的基础研究中,所有这些药物都通过双重机制发挥作用,即Ca^2+增敏和PDEIII抑制。第一种和第三种化合物的临床研究已经启动。第二种药物的独特之处在于,即使在动物模型中,它也没有变时作用,这可能是强心剂的重要性质。可从增加肌原纤维Ca^2+敏感性的化合物家族开发用于CHF患者的新型有效治疗剂。少
项目成果
期刊论文数量(18)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Endoh,M.: "The effects of various drugs on the myocardial inotropic response."Gen.. Pharmacol.. 26. 1-31 (1995)
Endoh,M.:“各种药物对心肌正性肌力反应的影响。”Gen.. Pharmacol.. 26. 1-31 (1995)
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
遠藤政夫: "The effects of various drugs on the myocardial inotropic response." Gen. Pharmacol.26. 1-31 (1995)
Masao Endo:“各种药物对心肌正性肌力反应的影响。Gen. Pharmacol.26 (1995)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
渡辺章: "Ca^<2+> sensitiger Org-30029 reverses acidosis-and BDM-induced contractile deprassion in canine myocardium." Am.J.Physiol.271. H1829-H1839 (1996)
Akira Watanabe:“Ca ^ 2+ 敏感剂 Org-30029 逆转犬心肌中酸中毒和 BDM 诱导的收缩抑制。”Am.J.Physiol.271(1996)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Kawabata,Y.: "EHects of a novel cardiotonic agent,Org9731,on force and acquorin tight transients in intract ventricular myocardium of the dog:involvement of a cyclic AMP-mediated mechanism and myofibrillar responsiveness to Ca^<2+> ions."J. Cardiac Failur
Kawabata,Y.:“一种新型强心剂 Org9731 对狗心室心肌内力和水母蛋白紧密瞬变的影响:循环 AMP 介导的机制和肌原纤维对 Ca^2 离子的反应的参与。”J
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Zhu,Y.: "Negative chronotropic and inotropic effects of andothelin isopeptides in mammalian cardiac muscle."Am. J. Physiol.. 273. H119-H127 (1997)
Zhu,Y.:“安多皮素异肽对哺乳动物心肌的负变时性和正性肌力作用。”Am。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ENDOH Masao其他文献
ENDOH Masao的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ENDOH Masao', 18)}}的其他基金
Molecular pharmacological research for regulation and disorder of cardiac myocytes
心肌细胞调控与紊乱的分子药理学研究
- 批准号:
16390064 - 财政年份:2004
- 资助金额:
$ 1.41万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Basic research for regulation and disorder of cardiac Ca signal
心脏Ca信号调控与紊乱的基础研究
- 批准号:
14370778 - 财政年份:2002
- 资助金额:
$ 1.41万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
MORECULAR PHARMACOLOGICAL STUDY OF SIGNAL TRANSDUCTION
信号转导的更常规药理学研究
- 批准号:
11470021 - 财政年份:1999
- 资助金额:
$ 1.41万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of Novel Therapeutic Agents for Treatment of Congestive Heart Failure by Means of Model Animals
通过模型动物开发治疗充血性心力衰竭的新型治疗剂
- 批准号:
11557203 - 财政年份:1999
- 资助金额:
$ 1.41万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of novel cardiotonic agents
新型强心剂的开发
- 批准号:
04557009 - 财政年份:1992
- 资助金额:
$ 1.41万 - 项目类别:
Grant-in-Aid for Developmental Scientific Research (B)
A Molecular Mechanism, of Myocardial alpha-Adrenoceptor-mediated Signaltransductio
心肌α-肾上腺素受体介导的信号转导的分子机制
- 批准号:
03454142 - 财政年份:1991
- 资助金额:
$ 1.41万 - 项目类别:
Grant-in-Aid for General Scientific Research (B)