A Placebo Controlled, Randomized, Double-Blind, Fixed-dose, Multicenter, Phase IIb Study to Investigate the Efficacy and Tolerability of BAY 58-2667 (50 µg/h, 100 µg/h, 150 µg/h) Given Intravenously to Subjects With Acute Decompensated Chronic Congestive Heart Failure (ADHF) Within 12 Hours After Hospital Admission (Pulmonary Artery Catheter eg, Swan-Ganz Not Required)

A placebo controlled, double-blind and randomized study to assess different doses of a new drug (BAY58-2667) given intravenously, to evaluate if it is safe and can help to improve the well-being of patients with acute decompensated heart failure.

开始日期2010-04-01

申办/合作机构

Bayer AG

NCT01065077

/ Terminated临床2期

A Placebo Controlled, Randomized, Double-Blind, Fixed-dose, Multicenter, Phase IIb Study to Investigate the Efficacy and Tolerability of BAY58-2667 (150 µg/h, 100 µg/h, 50 µg/h) Given Intravenously to Subjects With Acute Decompensated Chronic Congestive Heart Failure (ADHF)

开始日期2010-03-01

申办/合作机构

Bayer AG

NCT01067859

/ Terminated临床2期

A Placebo Controlled, Randomized, Double-Blind, Fixed-dose, Multicenter, Phase IIb Study to Investigate the Efficacy and Tolerability of Low Dose BAY58-2667 (25 µg/h, 10 µg/h) Given Intravenously to Subjects With Acute Decompensated Chronic Congestive Heart Failure (ADHF)

开始日期2010-03-01

申办/合作机构

Bayer AG

100 项与西那西呱相关的临床结果

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100 项与西那西呱相关的转化医学

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100 项与西那西呱相关的专利（医药）

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177

项与西那西呱相关的文献（医药）

2025-12-01·CELL CALCIUM

Neuronal regulation of myenteric interstitial cells of Cajal (ICC-MY) in the proximal colon

Article

作者: Thompson, Katy M ; Baker, Salah A ; Smith, Benjamin ; Sanders, Kenton M ; Drumm, Bernard T ; Karwa, Manushri

Interstitial cells of Cajal (ICC) generate contractile patterns of colonic motility. We investigated innervation of ICC within the plane of the myenteric plexus (ICC-MY) in proximal colon using mice expressing GCaMP6f in ICC. ICC-MY generated localized Ca²⁺ transients that couple to activation of ANO1 channels, a Ca²⁺-activated Cl^- conductance. ICC are electrically coupled to SMCs, so activation or suppression of currents in ICC affects excitability of SMCs. ICC-MY displayed tonic inhibition, as the neurotoxin, TTX, increased the frequency of Ca²⁺ transients. Tonic inhibition was mimicked by a nitric oxide donor, NONOate, and by a guanylate cyclase agonist (Bay 58-2667). In contrast ODQ mimicked effects of TTX, increasing Ca²⁺ transients. Carbachol (CCh) increased Ca²⁺ transients in ICC-MY, and these effects were mediated by M3 muscarinic receptors. Neostigmine, also increased Ca²⁺ transients, suggesting there is tonic activation of enteric excitatory neurons in colonic muscles. Substance P and antagonists of NK1 and NK2 receptors had no effect on Ca²⁺ transients in ICC-MY. Electrical field stimulation (EFS), under conditions that emphasized excitatory neural responses, enhanced Ca²⁺ transients, and these effects were blocked by atropine or an M3 receptor antagonist (DAU 5884). EFS in the presence of atropine caused inhibition of Ca²⁺ via release of NO. Cessation of nitrergic stimulation resulted in a substantial increase in Ca²⁺ transients, known as post-stimulus excitation. In summary, ICC-MY, important for the generation of propulsive contractions in the colon, are innervated by excitatory (cholinergic) and inhibitory (nitrergic) motor neurons, and these inputs regulate the excitability of these cells.

2025-08-01·Acta Physiologica

Lipocalin‐2 Restores Soluble Guanylyl Cyclase‐Dependent Dilation of the Afferent Arteriole After Renal Transplantation or Ex Vivo Hypoxia/Reoxygenation in Mice

Article

作者: Pfefferkorn, Anna Maria ; Persson, Pontus B. ; Erdogan, Cem ; Sauer, Igor Maximilian ; Khedkar, Pratik Hemant ; Xu, Minze ; Eigen, Marc ; Lichtenberger, Falk‐Bach ; Schwelberger, Hubert ; Aigner, Felix ; Lai, En Yin ; Wang, Pinchao ; Ashraf, Muhammad Imtiaz ; Zhao, Liang ; Patzak, Andreas ; Catar, Rusan

ABSTRACT:

Aim:

Dilatory microvascular function is impaired in ischemia/reperfusion injury in the kidney. Nitric oxide independent activators of soluble guanylyl cyclase (sGC) provide renal protection by dilating microvessels and preserving perfusion, but their efficacy declines after severe hypoxia. This study explores whether lipocalin‐2 (Lcn2), a key iron‐transporting protein, can restore the sGC‐mediated dilation in mouse afferent arterioles (AAs) after hypoxia/reoxygenation (H/R) and kidney transplantation.

Methods:

Dilation of isolated, angiotensin II (Ang II) pre‐constricted, AAs was induced by application of sGC activator cinaciguat after pre‐constriction with Ang II following H/R (H: 30 min, R: 10 min ± holo‐rLcn2, apo‐rLcn2, deferoxamine) and syngeneic kidney transplantation (cold ischemia: 30 min or 5.5 h, reperfusion: 20 h ± holo‐rLcn2) in C57BL/6 mice. To corroborate the dilatory function at the organ level, vascular relaxation was assessed using an isolated mouse kidney perfusion system.

Results:

Dilation of AAs was impaired following H/R. Pretreatment with holo‐rLcn2 (iron‐bound) preserved dilation, whereas apo‐rLcn2 (iron‐free) had no effect. The reversal of holo‐rLcn2's effect by deferoxamine confirmed the role of iron. AAs from kidney transplants showed reduced dilation compared to sham‐operated controls, with greater impairment following prolonged ischemia. Treatment with holo‐rLcn2 significantly improved dilatory function after extended cold ischemia (5.5 h), restoring it to levels seen with shorter ischemia (30 min). Ex vivo perfusion of the isolated mouse kidney with holo‐rLcn2 enhanced cinaciguat‐induced vascular relaxation, confirming its beneficial effect at the organ level.

Conclusion:

This study identifies a novel role for holo‐rLcn2 in preserving renal vascular function post‐H/R and kidney transplantation, apparently by upholding iron levels in vascular cells.

2025-06-02·Current Molecular Pharmacology

Stimulation of Soluble Guanylyl Cyclase (sGC) by Cinaciguat Attenuates Sepsisinduced Cardiac Injury

Article

作者: Li, Wanqian ; Wang, Binhui ; Chen, Guang ; Wang, Lingjun ; Lin, Ronghai ; Zheng, Cheng ; Zhang, Xijiang ; Shen, Enjian

Background::

Cinaciguat is a soluble Guanylyl Cyclase (sGC) activator that plays a crucial role in cardiovascular diseases. Previous research has shown that cinaciguat is involved in the progression of cardiomyopathy, which encompasses cardiac enlargement, heart dysfunction, and doxorubicin-induced heart damage. However, its therapeutic potential in sepsis-induced cardiomyopathy remains unknown.

Objectives::

This study examined the impact of cinaciguat on Lipopolysaccharide (LPS)-induced myocardial injury and the underlying molecular mechanisms.

Methods::

The mice model was established through intraperitoneal injection of LPS (10 mg/kg), and an in vitro model was generated by stimulating H9C2 cells with LPS (10 μg/ml) for 12 h. Subsequently, the sGC activator cinaciguat was used to assess its effects on LPS-induced cardiac injury. Additionally, echocardiography was conducted 12 hours after modeling to analyze cardiac function in mice. We used various methods to evaluate inflammation, and apoptosis, including Enzyme-Linked Immunosorbent Assay (ELISA), terminal deoxynucleotidyl transferase-mediated deoxyuridine Triphosphate Nick End Labeling (TUNEL) assay, Hematoxylin and Eosin (H&E) staining, western blotting and Real-Time Polymerase Chain Reaction (RT-PCR). Additionally, the protein kinase cGMP-dependent 1 (PRKG1)/cAMP-Response Element Binding protein (CREB) signaling pathway and Mitochondrial Ferritin (FtMt) in LPS-induced cardiac injury was assessed via Western blot analysis.

Results::

LPS-induced cardiac dysfunction and increased levels of cardiac injury markers Cardiac Troponin T (cTnT) in vivo . This change was accompanied by an increase in inflammatory cytokines through Interleu-1β (IL-1β), Tumor Necrosis Factor α (TNF-α), and Interleu-6 (IL-6). The expression of apoptosis, such as cleaved caspase-3, Bax, and Bcl-2, was also upregulated. However, these effects were reversed via treatment with cinaciguat. Additionally, cinaciguat alleviated LPS-induced cardiac inflammation and apoptosis by activating the PRKG1/CREB signaling pathway, and promoting FtMt expression. The same results were also obtained in H9C2 cardiomyocytes.

Conclusion::

We demonstrated that cinaciguat alleviated LPS-induced cardiac dysfunction, inflammation, and apoptosis through the PRKG1/CREB/FtMt pathway, thereby protecting against LPS-induced cardiac injury. This study identified a new strategy for treating cardiac injury caused by sepsis.

项与西那西呱相关的新闻（医药）

2023-03-10

·CPHI制药在线

研发 | 可溶性鸟苷酸环化酶激动剂对心血管的保护及对HFpEF的治疗作用机制

关注并星标CPHI制药在线一氧化氮( NO) 通路受损与多种心血管疾病密切相关，如心力衰竭、高血压和肺动脉高压等。NO供体药物或吸入 NO 在临床治疗中具有较大局限性，而近年来，随着NO-可溶性鸟苷酸环化酶( sGC) -环鸟苷酸( cGMP) 信号通路相关机制的研究深入，sGC 激动剂在心血管系统的临床应用得到了广泛开展。可溶性鸟苷酸环化酶（sGC）主要存在于血小板和血管平滑肌细胞中，是 NO-sGC-环鸟苷酸（cGMP）信号转导途径的中心环节。研究显示，NO-sGC-cGMP轴是调控心血管系统的关键信号转导途径，因此 sGC在心力衰竭、高血压和肺动脉高压等疾病的治疗中具有重要作用。sGC 对NO 具有高度亲和性，在内皮细胞中，炎症因子通过刺激内皮型一氧化氮合酶合成 NO，随之 NO 往深层次浸润，触及平滑肌细胞，从而激活 sGC，被激活的sGC 通过 C 端催化域促进第二信使 cGMP 过度分泌，继而引起一系列心血管反应，包括血管舒张、白细胞聚集和血小板活性增加等。而cGMP 分泌不足或活性减低则会引起内皮功能障碍、血管收缩、血管僵硬和不良重构，以及肾和冠状动脉血流减少。所以sGC 激动剂通过活化下游的cGMP 在抗心肌缺血，改善左心室重塑，改善心力衰竭，抑制炎症和纤维化，改善代谢等方面具有重要作用。 sGC 激动剂对心血管的保护机制可溶性鸟苷酸环化酶激动剂通过活化下游的环鸟苷酸在抗心肌缺血和抗心力衰竭，改善左心室重塑，降低肺动脉压力，抑制炎症和纤维化，改善心肌代谢等方面发挥重大作用。①改善缺血再灌注损伤。sGC激活剂 cinaciguat预处理可减少心肌细胞的坏死和凋亡，减少心肌梗死面积，还可改善低温体外循环心脏停跳术后的心肌和内皮功能，对心肌缺血再灌注损伤起到重要保护作用。此外，研究发现经sGC激活剂 cinaciguat预处理的供体心脏，在进行心脏移植后心脏的左心室功能得到明显改善。研究显示刺激 NO-GC-cGMP 通路的药物依赖于心肌细胞的大电导钙离子激活钾( BK) 通道，可发挥缺血再灌注的相关心脏保护作用，心肌细胞缺少 BK 通道使心脏更易发生缺血再灌注损伤，增加BK活性有利于缺血再灌注心肌的存活。②抗心力衰竭和改善心脏重构。大量的基础研究也相继证实 sGC 激动剂具有抑制心肌纤维化，改善心肌肥厚和心室重塑等心脏保护作用。sGC激活剂 cinaciguat可通过增加蛋白激酶 G(PKG) 的活性，选择性抑制心肌纤维化、氧化应激和心肌细胞的凋亡，进而改善左心室重塑。另外，cinaciguat 可通过阻止糖尿病大鼠模型心脏结构和分子的改变，进而改善心脏功能。③改善心肌代谢效率。研究显示，给予sGC激活剂riociguat 处理后，实验动物的冠状动脉阻力和全身血管阻力均有显著下降，riociguat可明显提高健康幼猪的心脏代谢效率。④降低肺动脉压力和抑制肺血管重塑。研究证实 sGC 激动剂可降低肺动脉压力和阻力，抑制肺血管重塑，提高肺动脉高压患者的运动耐量。2013 年riociguat 被 FDA 批准用于动脉性肺动脉高压和慢性血栓栓塞性肺动脉高压且世界卫生组织心功能分级为Ⅱ～Ⅲ级的患者，取得良好的临床治疗效果。⑤减轻炎症。sGC激活剂 cinaciguat 除了减少炎症和氧化应激，改善心肌细胞功能，还可调节 sGC-cGMP-PKG 信号通路，使肥厚相关激酶钙离子/钙调素依赖性蛋白激酶Ⅱ、蛋白激酶 C和细胞外信号调节激酶2活性正常化，这表明cinaciguat不仅改善心力衰竭，也是心肌肥厚患者的潜在治疗选择。 sGC 激动剂在射血分数保留性心力衰竭（HFpEF）中的作用机制 NO-sGC-cGMP 信号在心血管系统中起着核心作用，特别是在肺动脉高压、高血压和心衰方面。HFpEF是左室舒张期主动松弛功能受损和心肌顺应性降低，即室壁僵硬度增加导致左室舒张期充盈受损、每搏输出量减少和舒张末压增高而发生的心衰。sGC 激动剂在 HFpEF 中的作用机制尚未完全阐明，目前已知的病理生理机制主要包括以下方面：①舒张功能改变。sGC 可降低肌丝钙敏感性，并对跨桥分离产生有益影响，这与NO增加cGMP 生成和加速左室舒张的作用一致，而cGMP 依赖性蛋白激酶的激活，有利于改善心室肥大、舒张和僵硬。②收缩功能改变。在心肌中，sGC 能调节收缩力并减弱肾上腺素能刺激，除了心肌效应外，心脏内皮功能障碍的逆转也能改善舒张功能。③心脏结构变化。靶向 cGMP 信号通路的药物 sGC 激动剂有抗高血压作用，在不影响血压的剂量下可有利地改善心脏重构并减轻心肌纤维化。④依赖 cGMP 的蛋白激酶磷酸化。肌动蛋白是一种锚定在肌节Z线的蛋白质，是心肌被动张力和僵硬度的主要决定因素，可通过磷酸化来调节，这种翻译后修饰促进了肌联蛋白的被动张力的降低，因此有希望成为降低心肌僵硬的治疗靶点。⑤血管功能和硬度改变。HFpEF 患者在运动时全身血管舒张功能明显受损，限制了应激状态下心输出量，表现出血流介导的血管舒张受限。NO 依赖性调节是血管张力的重要调节因素，心衰患者 NO生物利用度的降低导致血管收缩和血管僵硬，进而增加后负荷，同时，NO 生物利用度降低也可能上调交感神经驱动和促进儿茶酚胺释放，并增强内皮素-1诱导的血管收缩。⑥肺动脉高压。在左室射血分数正常的老年患者中，HFpEF 是肺动脉压力升高的最常见原因，肺动脉压升高也预示着 HFpEF 死亡率增加。舒张功能障碍和肺动脉高压之间的显著重叠，研究证实，对肺动脉高压有效的 sGC 激动剂对 HFpEF 也有益。 sGC 激动剂在治疗心力衰竭和肺动脉高压等心血管疾病中具有良好的效果，也是未来心脏缺血再灌注损伤、心肌肥厚和心肌代谢异常等疾病临床治疗的潜在选择。随着对 NO-sGC-cGMP 轴的深入认识和 sGC 的作用机制研究，sGC 激动剂将为心血管疾病的治疗提供了更多的药物选择。在现有的基础上，sGC 激动剂的临床安全性和有效性得到了一定程度的肯定。事实证明，由 sGC激动剂触发 cGMP 的产生可能对心血管疾病的治疗具有更为广阔的市场前景。参考来源： [1]王喜梅,吴永健.可溶性鸟苷酸环化酶激动剂的心血管保护作用研究进展[J].心血管病学进展,2021,42(05):404-407. [2]陆军,金杰妮,王慧,胡静静,俞晴,蔡兆斌.可溶性鸟苷酸环化酶激动剂治疗慢性心力衰竭临床应用进展[J].浙江医学,2021,43(22):2492-2496. [3]贾晓艳,安晋阳,彭可玲,刘永铭.可溶性鸟苷酸环化酶激动剂治疗射血分数保留性心力衰竭的研究进展[J].心血管病学进展,2022,43(02):141-145. 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。智药研习社近期线下研习会报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

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100 项与西那西呱相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D07577	西那西呱	-	DB16126

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
失代偿性慢性心力衰竭	临床2期	美国	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	加拿大	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	克罗地亚	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	捷克	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	爱沙尼亚	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	德国	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	匈牙利	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	以色列	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	意大利	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	立陶宛	Bayer AG	2007-12-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00559650 (Pubmed \| Eur Heart J)	临床2期	急性失代偿性心力衰竭	139	Cinaciguat	遞繭襯鹹鹹鬱獵遞醖積(範簾遞蓋膚齋壓製淵繭) = the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h 選觸觸積襯鬱衊鹹襯繭 (願餘顧齋窪願齋構壓憲 )	-	2013-01-01
				Placebo