Randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide.

开始日期2023-08-10

申办/合作机构

Yale University

[+1]

NCT05125237 / Active, not recruitingN/AIIT

Data Analysis for Drug Repurposing for Effective Alzheimer's Medicines (DREAM)- Amiloride vs Triamterene

This study aims to evaluate the comparative risk of dementia/Alzheimer's disease onset between patients treated with medications that target specific metabolic pathways and patients treated with alternative medications for the same indication.

开始日期2021-10-01

申办/合作机构

The Brigham & Women's Hospital, Inc.

[+3]

NCT04331691 / Recruiting临床4期IIT

SPironolactone Versus Amiloride for Treatment of REsistant Hypertension (SPARE Trial): A Comparison of Home Blood Pressure

Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes including diuretics. Patients with resistant hypertension has at least 1.5-fold higher cardiovascular risk than those with non-resistant hypertension. Therefore, controlling blood pressure is crucial in patients with resistant hypertension.
It has been unclear which antihypertensive agent should be added in patients who cannot reach target blood pressure despite use of three antihypertensive agents. There have been three randomized clinical trials that proved the efficacy of spironolactone in resistant hypertension, but they were small sized, comparison study to placebo. Recently published PATHWAY-2 study which compared the efficacy of spironolactone with placebo, doxazosin, and bisoprolol showed superiority of spironolactone in blood pressure lowering in patients with resistant hypertension. Thus, revised ACC/AHA and ESC/ESH guideline for arterial hypertension recommended spironolactone as the fourth agent for resistant hypertension. However, in real world, adherence to spironolactone may not be adequate because of adverse effect such as gynecomastia, hyperkalemia, and so on.
Recently, sub-study of PATHWAY-2 revealed that amiloride changes systolic blood pressure by -22.2 mmHg (95% CI, -24.7 to -19.7) which is comparable with the effect of spironolactone (-21.8 mmHg; 95% CI, -24.2 to -19.3). However, it was not randomized clinical trial to compare the effect between spironolactone and amiloride in patients with resistant hypertension.
This study aims to compare the effect of spironolactone and amiloride on home blood pressure in resistant hypertensive patients and to compare the rate of target blood pressure achievement between spironolactone and amiloride in resistant hypertensive patients.

开始日期2020-11-16

申办/合作机构

Yonsei University

100 项与盐酸阿米洛利相关的临床结果

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100 项与盐酸阿米洛利相关的转化医学

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100 项与盐酸阿米洛利相关的专利（医药）

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项与盐酸阿米洛利相关的文献（医药）

2024-03-01·Theriogenology

Acidosis defense mechanisms in the preimplantation stages of embryos in BALB/c strain mice

Article

作者: Tuli, Abdullah ; Dundar-Yenilmez, Ebru ; Dagilgan, Senay ; Urunsak, Ibrahim Ferhat ; Erdogan, Seref

Regulation of intracellular pH (pH_i) is an important homeostatic function of cells. There are three major pH_i regulatory mechanisms: the HCO₃^-/Cl^- exchanger (AE), which alleviates alkalosis, and the Na⁺/H⁺ exchanger (NHE) and Na⁺,HCO₃^-/Cl^- exchanger (NDBCE), both of which counteract acidosis. NHE activity, which is high at the germinal vesicle stage of oocyte, is inhibited during meiotic maturation, while this inhibition is abolished when the oocyte reaches the pronuclear (PN) stage of the zygote. On the other hand, we have previously found that NDBCE performs complementary regulation against acidosis during meiotic maturation. Additionally, we found that AE activity, which is a defense mechanism against alkalosis, gradually decreases during preimplantation period of embryonic development. Considering that NHE activity is inhibited during meiotic maturation and AE activity gradually decreases during embryonic development stages, we investigated whether NHE and NDBCE activities, both of which act against acidosis, functionally change from the PN zygote to the blastocyst stage of the embryo and identified these pH-regulating proteins at the molecular level in mice of the Balb/c strain. PN zygotes, two-cell (2-c), four-cell (4-c), morula and blastocyst stage embryos were obtained from 5-8-week-old, sexually mature female Balb/c mice by using the classical superovulation procedure. pH_i was recorded by using the microspectrofluorometric technique on zygotes and embryos simultaneously loaded with the pH-sensitive fluorophore, 2',7'-Bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). The activities of NHE and NDBCE were determined from the recovery curve of induced-acidosis in bicarbonate-free and bicarbonate-containing media, respectively. Specific inhibitors such as cariporide (1 μM), S3226 (1 and 10 μM), EIPA (1, 5, and 25 μM), and amiloride (1 mM) were used to functionally identify NHE isoforms, and the nonspecific inhibitor 4,4'-diisocyanatostilbene-2,2' disulphonic acid, disodium salt (DIDS) was used to confirm NDBCE activity. The isoforms of the pH_i-regulatory proteins were also identified by molecular biology using real-time PCR. We found that NHE activity was high at all embryonic stages, and differences between stages were not significant. Functional and molecular findings indicated that isoforms of NHE 1 and 5 are present in the blastocyst, whereas isoforms of NHE 1, 3, and 4 are functional at earlier embryonic stages. Although the contribution of NDBCE activity to recovery from induced-acidosis was detected at all embryonic stages, it was significant only in the PN zygote and the 2-c embryo. This finding was confirmed by molecular analysis, which detected the expression of SLC4A8 encoding NDBCE at all embryonic stages. In conclusion, NHE is an active and important defense mechanism against acidosis and is encoded by at least two protein isoforms in all stages of the Balb/c strain of mice. NDBCE has a supportive function in all embryonic stages, especially in the PN zygote and the 2-c embryo. Preimplantation stage embryos have effective mechanisms to defend against acidosis in response to their metabolic end products (increased acid load) and the acidic environment in utero.

2024-03-01·International Journal of Pharmaceutics

Dual fluorescence images, transport pathway, and blood–brain barrier penetration of B-Met-W/O/W SE

Article

作者: Li, Junying ; Cheng, Hongyan ; Liu, Huanhuan ; Zhang, Caiyun ; Fang, Liang

Borneol is an aromatic traditional Chinese medicine that can improve the permeability of the blood-brain barrier (BBB), enter the brain, and promote the brain tissue distribution of many other drugs. In our previous study, borneol-metformin hydrochloride water/oil/water composite submicron emulsion (B-Met-W/O/W SE) was prepared using borneol and SE to promote BBB penetration, which significantly increased the brain distribution of Met. However, the dynamic images, transport pathway (uptake and efflux), promotion of BBB permeability, and mechanisms of B-Met-W/O/W SE before and after entering cells have not been clarified. In this study, rhodamine B and coumarin-6 were selected as water-soluble and oil-soluble fluorescent probes to prepare B-Met-W/O/W dual-fluorescent SE (B-Met-W/O/W DFSE) with concentric circle imaging. B-Met-W/O/W SE can be well taken up by brain microvascular endothelial cells (BMECs). The addition of three inhibitors (chlorpromazine hydrochloride, methyl-β-cyclodextrin, and amiloride hydrochloride) indicated that its main pathway may be clathrin-mediated and fossa protein-mediated endocytosis. Meanwhile, B-Met-W/O/W SE was obviously shown to inhibit the efflux of BMECs. Next, BMECs were cultured in the Transwell chamber to establish a BBB model, and Western blot was employed to detect the protein expressions of Occludin, Zona Occludens 1 (ZO-1), and p-glycoprotein (P-gp) after B-Met-W/O/W SE treatment. The results showed that B-Met-W/O/W SE significantly down-regulated the expression of Occludin, ZO-1, and P-gp, which increased the permeability of BBB, promoted drug entry into the brain through BBB, and inhibited BBB efflux. Furthermore, 11 differentially expressed genes (DEGs) and 7 related signaling pathways in BMECs treated with B-W/O/W SE were detected by transcriptome sequencing and verified by quantitative real-time polymerase chain reaction (qRT-PCR). These results provide a scientific experimental basis for the dynamic monitoring, transmembrane transport mode, and permeation-promoting mechanism of B-Met-W/O/W SE as a new brain-targeting drug delivery system.

2024-03-01·Journal of Hazardous Materials

Silica nanoparticles inhibit cadmium uptake by the protozoan Tetrahymena thermophila without the need for adsorption

Article

作者: Miao, Ai-Jun ; Pan, Ke ; Yang, Liuyan ; Wu, Chao ; Yue, Tongtao ; Pan, Wei ; Zhang, Jia-Xin ; Deng, Chaofan ; Tan, Qiao-Guo

The simultaneous presence of nanoparticles (NPs) and heavy metals in the environment may affect their mutual biological uptake. Although previous studies showed that NPs could alter the cellular uptake of heavy metals by their adsorption of heavy metals, whether they could affect metal uptake without the need for adsorption is unknown. This study examined the effects of silica (SiO₂) NPs on the uptake of Cd ion by the protozoan Tetrahymena thermophila. We found that, even with negligible levels of adsorption, SiO₂ NPs at concentrations of 3 to 100 mg/L inhibited Cd uptake. This inhibitory effect decreased as the ambient Cd concentration increased from 1 to 100 μg/L, suggesting the involvement of at least two transporters with different affinities for Cd. The transporters were subsequently identified by the specific protein inhibitors amiloride and tariquidar as NCX and ABCB1, which are responsible for the uptake of Cd at low and high Cd levels, respectively. RT-qPCR and molecular dynamics simulation further showed that the inhibitory effects of SiO₂ NPs were attributable to the down-regulated expression of the genes Ncx and Abcb1, steric hindrance of Cd uptake by NCX and ABCB1, and the shrinkage of the central channel pore of the transporters in the presence of SiO₂ NPs. SiO₂ NPs more strongly inhibited Cd transport by NCX than by ABCB1, due to the higher binding affinity of SiO₂ NPs with NCX. Overall, our study sheds new light on a previously overlooked influence of NPs on metal uptake and the responsible mechanism.

项与盐酸阿米洛利相关的新闻（医药）

2023-11-23

·生物制品圈

首次！靶向“饥饿”癌细胞！港大最新研究：揭示癌症治疗新策略

导读：为了在营养匮乏的肿瘤微环境中生长，癌细胞通常会内化和降解细胞外蛋白以补充细胞内氨基酸。然而，既往研究报道的营养获取途径主要局限于自噬-溶酶体途径。目前尚不清楚其他蛋白质降解系统是否也有助于细胞外营养物质的利用。 11月20日，香港大学汪卫平团队在期刊《Advanced Science》上发表题为“Amino Acid-Starved Cancer Cells Utilize Macropinocytosis and Ubiquitin-Proteasome System for Nutrient Acquisition”的研究论文，研究证明，在氨基酸饥饿下，通过巨胞饮作用的细胞外蛋白质内化和通过泛素-蛋白酶体系统的蛋白质降解被激活为营养供应途径，使癌细胞对蛋白酶体抑制敏感。通过抑制巨胞饮作用和泛素-蛋白酶体系统，提出了一种加强癌症治疗氨基酸饥饿的创新方法。作为全球主要死亡原因之一，癌症的特点是细胞增殖不受控制，具有高度进展性。实体瘤通常超过其血液供应，并形成缺乏营养物质（如氨基酸和葡萄糖）的肿瘤微环境。作为体液中最丰富的有机成分，蛋白质有可能作为替代资源，因为每种蛋白质都可以提供数个数量级的大量氨基酸。因此，癌细胞会制定利用细胞外蛋白的策略。例如，在氨基酸饥饿下，细胞外蛋白通过巨胞饮作用内化。哺乳动物雷帕霉素靶标（mTOR）信号通路被抑制，mTOR 复合物 1（mTORC1）从溶酶体膜中释放，导致溶酶体上的液泡型H ATP酶（V-ATPase）组装。作为活性质子泵，这些V-ATP酶可降低溶酶体pH值，以增加蛋白酶活性并促进溶酶体降解蛋白质含量。mTOR活性降低也会触发Unc51样激酶1/2激活，增强自噬体形成和自噬蛋白降解。然而，先前研究证明的营养获取途径主要局限于自噬-溶酶体系统。目前尚不清楚其他蛋白质降解途径是否也在细胞外蛋白质的利用中发挥重要作用。在这项研究中，除了传统的溶酶体途径进行细胞外蛋白质利用外，我们发现巨胞饮作用-UPS轴可以作为细胞外蛋白质内化和降解的另一种途径。研究显示，饥饿的癌细胞对UPS抑制变得更加敏感。因此，UPS可以作为癌症饥饿治疗的新靶点。我们的结果表明，蛋白酶体抑制增强了蛋白质内化作为反馈，这可能通过自噬降解提供补充营养。基于巨胞饮作用-UPS轴作为氨基酸补充途径，我们假设同时抑制巨胞饮作用和蛋白酶体可以显着加剧氨基酸饥饿。因此，我们探索了UPS抑制剂硼替佐米（BTZ）和巨胞饮抑制剂5-（N-乙基-n-异丙基）-阿米洛利（EIPA）联合治疗癌症的潜力。为了共同递送疏水性药物BTZ和亲水性药物EIPA，开发了一种pH响应性聚合物递送系统，以进一步增强药物在肿瘤组织中的积累并控制癌细胞中的药物释放。与之前消耗葡萄糖或阻断氨基酸转运蛋白的纳米药物形成鲜明对比的是，我们首次开发了一种靶向蛋白质分解代谢的配位纳米载体，作为基于饥饿的癌症治疗的有前途的策略（图1）。示意图。描绘了负载有 BTZ 和 EIPA 的 pH 响应性聚合物体耗尽细胞内氨基酸用于癌症饥饿治疗。综上所述，除了传统的溶酶体途径进行细胞外营养利用外，我们发现巨胞饮作用-UPS轴可以作为氨基酸供应的另一种细胞外蛋白质降解过程，以支持癌细胞存活。饥饿的癌细胞对BTZ表现出更高的敏感性。因此，我们将BTZ与巨胞饮抑制剂EIPA联合使用，以同时阻断蛋白质内化和UPS依赖性降解，通过避免代偿性蛋白质分解代谢来达到协同抗癌作用。为了促进该策略的临床转化，开发了一种pH响应性聚合物体来共同递送这两种药物，从而增强药物在肿瘤组织中的保留并提高治疗效果。通过靶向蛋白质分解代谢过程，这项研究为癌症饥饿治疗提供了新的见解。参考资料：https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202304791 内容来源于网络，如有侵权，请联系删除。

2022-11-26

·药智网

抗高血压新药简史

1628年，威廉·哈维在《心血运动论》一书中，描述了血液循环的过程，首次系统地阐述了他对心血管系统的理解。到了1733年，英国牧师Stephen Hales首次公布了他测量的血压数值；1808年，托马斯·杨，提出了高血压的概念，并认为高血压是一种疾病。后来，医生们注意到心脏肥大和肾脏疾病以及高血压之间的联系，认为肾脏血管增厚，可能是对血压升高的一种适应。1874年，弗雷德里克第一次报道了没有肾脏疾病的人，血压也可以升高。这一概念的普及要归功于克利福特·奥尔巴特。1896年，他在一系列报告中，指明了血压升高但没有肾脏疾病证据的临床病例，并把这种疾病定义为“一种独立于肾脏的疾病，它有自己的特点，其中高的动脉血压，收缩压和舒张压，似乎是最主要的。”他把这种疾病，称为高血压症。图1 克利福特·奥尔巴特来源：参考文献1抗高血压新药简史高血压，被认为是心血管疾病死亡和心血管疾病住院的主要和普遍的原因之一。它被认为是一个高度相关的危险因素，而不是一个风险中介。已有证据表明，降低血压可以减少诸如中风、心肌梗塞和心血管死亡等疾病。正如威廉·哈维早期所认识到的那样，器官灌注被认为是取决于血压。很长一段时间以来，人们对降低血压是否有用并不确定。John Hay在1931年写道：“高血压往往是成功的惩罚……”。他在结论部分指出“对高血压患者来说，最大的危险在于其被发现，因为那时一定会有一些傻瓜试图降低血压。”但可以确定的是，血压升高与结果密切相关，特别是恶性血压（舒张压超过110毫米汞柱），导致1年后的死亡率达到80%，而在使用利尿剂后，死亡率明显降低，降压药的潜在用途得到了仔细研究。图2 1939年未接受治疗、1981年接受利尿剂治疗的抵抗性高血压患者的生存率来源：参考文献4高血压的治疗方案，包括营养学、交感神经阻断、使用药物等。第一个降压饮食的经验是由Kempner提出的，他引入了一种营养方案，包括水果、果汁和米饭，其中最受关注的是盐。减少盐分吸收是预防高血压和其他心血管疾病的一种经济、安全的方法。但是，个人减盐似乎很困难，通过利尿剂可能更容易实现。Carl Ludwig首次证明了交感神经系统，在循环系统调节中的作用，特别是肾脏的作用。这促使人们首次尝试通过外科手术中断交感神经的支配来降低血压。这些手术伴随着较高的死亡率和严重的副作用，以及因直立性低血压、晕厥、勃起功能障碍和尿失禁而再次住院。目前，降压药的使用，是控制高血压最有效的手段。关于利尿剂的使用，可以追溯到20世纪初。医生观察到用于治疗梅毒的药物Merbaphen（Novasurol®）能增加利尿，这一发现被德国Hoechst公司进一步发展为另一种含汞的利尿剂Mersalyl（Salyrgan®），它在30多年里，一直是一种标准的利尿剂。后来，氯噻嗪、呋塞米，以及保钾利尿剂如阿米洛利和螺内酯相继问世。后来，β-受体阻滞剂如普萘洛尔、肾素-血管紧张素系统抑制剂如缬沙坦、钙离子通道阻断剂硝苯地平等相继被开发出来。这些药物为血压控制提供了强有力的保障。图3 降压药物类别及作用机制来源：参考文献51981年，比利时安特卫普大学的Paul M.Vanhoutt以及后来的其他研究人员，相继报道了报告了内皮细胞释放的血管收缩物质。20世纪80年代中期，日本筑波大学的博士生柳泽正志发现了相关研究，并注意到这种血管收缩物质的分子到底是什么，还没有被确定，因此将其鉴定作为了博士论文课题。后藤克俊和生物化学家木村贞夫的小组，也成为该项目的一部分。该项目采用了“前基因组时代的蛮力生物化学”，由木村贞夫领导。到1987年9月，前内皮素-1基因被克隆，多肽被测序。随后，重组内皮素-1（ET-1）被合成，其血管收缩活性在体外和体内得到证实。内皮素-1（ET-1）是一种由血管内皮产生的21个氨基酸的肽。它是一种非常有力的血管收缩剂，与平滑肌内皮素受体结合，其中有两种亚型。ETA和ETB受体。这些受体与Gq蛋白偶联，受体激活导致IP3的形成，从而引起肌浆网（SR）释放钙，增加平滑肌的收缩和血管收缩。还有位于内皮的ETB受体，刺激一氧化氮的形成，在没有平滑肌ETA和ETB受体激活的情况下产生血管扩张。图4 内皮素-1（ET-1）影响血管平滑肌的作用机制来源：参考文献6由于ET-1具有强大的血管收缩特性和对细胞内钙的影响，它被认为与高血压、冠状动脉血管痉挛和心力衰竭的发病机制有关。一些研究表明，ET-1在特发性肺动脉高压以及全身性高血压中的作用。内皮素受体拮抗剂通过阻断ET-1的血管收缩和强心作用，产生血管扩张和心脏抑制。内皮素受体拮抗剂已被证明在心力衰竭的实验模型中，能降低死亡率并改善血流动力学。目前，内皮素拮抗剂的一个批准适应症是肺动脉高压，例如波生坦（Bosentan）是一种非选择性的ET-1受体拮抗剂（阻断ETA和ETB受体）；马西坦（Macitentan）是一种类似的非选择性拮抗剂，但其半衰期比波生坦长。另一种也用于治疗肺动脉高压的药物是安贝生坦（Ambrisentan），它是一种选择性ETA受体拮抗剂。30年来，首个创新高血压药来了？随着时间的推移，抗高血压新药的研发从未止步。2022年5月，Idorsia公司宣布，和杨森联合开发的潜在“first-in-class”双重内皮素受体拮抗剂Aprocitentan，在治疗顽固性高血压患者的3期临床试验中获得积极顶线结果。11月，公布了Aprocitentan最新的III期临床试验（PRECISION）结果。PRECISION是一项多中心、盲法、随机、平行分组的3期研究，在欧洲、北美、亚洲和澳大利亚的医院或研究中心进行。图5 Aprocitentan III期临床试验结果来源：参考文献7PRECISION的研究，从2018年6月18日开始，到2022年4月25日结束。1965人接受了筛选，730人被随机分配。在这730名患者中，704名（96%）完成了研究的第一部分；其中613名（87%）完成了第二部分，其中577名（94%）完成了研究的第三部分。Aprocitentan 12-5毫克在4周时，办公室收缩压的最小平方平均值（SE）变化为-15.3（SE 0.9）毫米汞柱，Aprocitentan 25毫克为-15.2（0.9）毫米汞柱，安慰剂为-11.5（0.9）毫米汞柱。与安慰剂相比，差异为-3.8（1.3）毫米汞柱（97.5%CI-6.8至-0.8，P=0.0042）和-3.7（1.3）毫米汞柱（-6.7至-0.8。p=0.0046）。24小时流动收缩压的差异分别为-4.2毫米汞柱（95%CI-6.2至-2.1）和-5.9毫米汞柱（-7.9至-3.8）。停药4周后，安慰剂与Aprocitentan相比，办公室收缩压（OSBP）明显升高（5.8毫米汞柱，95%CI 3.7至7.9，P<0.0001）。最常见的不良事件是轻度至中度水肿或液体潴留，在4周的双盲期中，接受Aprocitentan 12.5毫克、25毫克和安慰剂的患者分别发生了9%、18%和2%。这一事件，导致7名接受Aprocitentan治疗的患者停药。在试验期间，共发生了11起治疗突发的死亡事件，研究者认为这些事件都与研究治疗无关。图6 试验期间各组血压变化来源：参考文献6总的来说，这项III期研究结果表明，与安慰剂相比，在初始治疗4周后，添加Aprocitentan可降低标准化的自动办公室血压和24小时流动血压。在48周的时间里，为治疗耐受性高血压患者提供了有临床意义的SBP和DBP的降低，且不良反应可控。优秀的临床试验数据，使得市场十分看好这款药物。更有媒体指出，如果这款药物最终获批，将成为30年来首个基于新机制的降血压药物。高血压市场几何？回到市场方面。我国原发性高血压药物市场销售规模呈稳步增长态势，国内原发性高血压药物市场份额，也由2013年的434亿元，飞速扩张到2019年的840.8亿元。预计2026年，市场规模将达到1547.01亿元。图7 我国原发性高血压治疗药物市场规模（亿元）来源：民生证券研究报告数据显示，中国抗高血压药物市场呈现三足鼎立局势，钙离子通道阻滞剂销售占比超过30%，血管紧张素II受体拮抗剂销售占比超过20%，复方制剂占比超过15%，三类药物占据了将近70%的市场份额。但是，由于集采降价以及复方类药物价格优势，地平类和沙坦类终端市场份额略有下降，但总体维持在较高水平。图8 各类常见抗高血压药物市场份额来源：民生证券研究报告因此，目前我国抗高血压物还是以钙离子通道拮抗剂、ARB、ACEI类等药物为主。Aprocitentan代表了新一类降压药，是一种创新口服双重内皮素受体拮抗剂。它具有很长的半衰期，以及低药物-药物相互作用，其作用机制适合治疗难治性高血压，它是一种新型的、有效的、耐受性良好的治疗抵抗性高血压的方法。小结血液是人体能量最辛勤的运输队，没有心血的不倦循环，我们的生命就无法持久，正常的血压是保证器官获得充足血液灌注的必备条件。然而，随着生活水平、习惯的改变，高血压逐渐成为人类健康的最重要的威胁之一。经过几百年的发展，从解剖到分子机制的认识，让人们逐渐了解到高血压背后的秘密，正是这一步一步的细致入微的观察、探索，造就了一个个经典的抗高血压药物。相信随着高血压发病机制的揭示，会有更多创新性抗压药物诞生，造福更多的患者。参考文献1.Keynes M,Butterfield J.Sir Clifford Allbutt:Physician and Regius Professor 1892–1925.Journal of Medical Biography.1993;1(2):67-75.2.Barton M,Yanagisawa M.Endothelin:30 years from discovery to therapy[J].Hypertension,2019,74(6):1232-1265.3.Vignon-Zellweger N,Heiden S,Miyauchi T,et al.Endothelin and endothelin receptors in the renal and cardiovascular systems[J].Life sciences,2012,91(13-14):490-500.4.Wolf M,Ewen S,Mahfoud F,et al.Hypertension:history and development of established and novel treatments[J].Clinical Research in Cardiology,2018,107(2):16-29.5.Laurent S.Antihypertensive drugs[J].Pharmacological research,2017,124:116-125.6.https://www.cvphysiology.com/Blood%20Flow/BF0127.Schlaich M P,Bellet M,Weber M A,et al.Dual endothelin antagonist aprocitentan for resistant hypertension(PRECISION):a multicentre,blinded,randomised,parallel-group,phase 3 trial[J].The Lancet,2022.8.民生证券声明：如需转载，请务必注明文章作者和来源。如涉及作品内容、版权和其它问题，请您留言，我们将在第一时间删除。责任编辑 | 八角转载开白 | 马老师 18323856316（同微信）药智网原创作品 | 尽情分享朋友圈 | 转载请联系授权— Tips —如果您有医药行业相关的线索或对医药政策、研发创新、资本市场、行业发展有深度观察欢迎投稿给我们马老师 18323856316（同微信）邮箱：maxuelian@yaozh.com 阅读原文，是受欢迎的文章哦

2022-06-27

·Science Daily

Chemically modified plant compounds work against hepatitis E virus

Hepatitis E virus (HEV) is widespread, and so far there is no effective drug. In the search for one, the so-called rocaglates have come into focus: plant compounds that can inhibit the replication of viruses. Researchers have examined a library of chemically modified rocaglates for their antiviral effect. One group of active ingredients in particular stood out, a so-called amidino group. It was particularly effective in inhibiting viral replication. Hepatitis E virus (HEV) is widespread, and so far there is no effective drug. In the search for one, the so-called rocaglates have come into focus: plant compounds that can inhibit the replication of viruses. Researchers from the Department of Molecular and Medical Virology at Ruhr Universität Bochum (RUB) have examined a library of chemically modified rocaglates for their antiviral effect, which was developed by a team from Boston. One group of active ingredients in particular stood out, a so-called amidino group. It was particularly effective in inhibiting viral replication. Plant compounds inhibit proliferation of cancer cells and viruses Rocaglates are a group of plant substances produced by various mahogany plants. They are known to have an inhibitory effect on the proliferation of some cancer cells. It was not until 2008 that findings on their antiviral effect against RNA viruses were published for the first time: for example, they can inhibit the replication of Ebola viruses, HEV, Zika viruses and also Sars-Cov-2. The Boston team led by Professor John Porco Jr. has created a library of rocaglates with various chemical modifications. "The core structure of the total of 205 substances is always the same, and chemical groups of different sizes or flexibility have been attached to them," explains Mara Klöhn. The Bochum group tested these 205 substances for their effectiveness against HEV in cell culture. To do this, the researchers used cancer cell lines and HEV genomes tagged with a reporter gene. Based on the amount of protein produced, whose blueprint is located in this reporter gene, they can precisely measure how successfully the virus replicates in the presence of various substances. Modified rocaglates have a stronger effect than natural ones The researchers used a so-called half-maximum inhibitory concentration to indicate how strongly a substance inhibits viral replication. The lower it is, the better the substance works. "The half-maximum inhibitory concentration of our three-best tested rocaglates is between 0.5 and 3 nanomolar," reports Mara Klöhn. "By comparison, that of the natural rocaglamide silvestrol is three to seven nanomolar." A common feature of the top 3 rocaglates is an attached amidino group. Because rocaglates also have a cell-damaging effect that is particularly noticeable in cancer cells, the researchers also studied this toxicity in healthy porcine liver cells. "Here, the toxicity was lower than in cell culture, which is, after all, based on cancer cell lines," says Mara Klöhn. Further studies would have to examine the efficacy and toxicity of the most successfully tested substances in the organism. "We could also try to further chemically optimize the best amidino rocaglates so that they have an even stronger effect against viral replication," she says, looking optimistically to the future. Hepatitis E The hepatitis E virus is the main cause of acute viral liver infections. An estimated 20 million people worldwide contract the disease every year, and around 70,000 of them die. Acute infections usually self-limiting in affected individuals with an intact immune system. In people with reduced or suppressed immune systems, such as organ transplant recipients or HIV-infected patients, HEV can become chronic. HEV is also particularly threatening to pregnant women. Ribavirin is the only agent currently in use, but it is not effective in all cases.

100 项与盐酸阿米洛利相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D00649	盐酸阿米洛利	C03DB01	DB00594

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适应症	国家/地区	公司	日期
心脏衰竭	美国	Padagis US LLC	1981-10-05
高血压	美国	Padagis US LLC	1981-10-05

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适应症	最高研发状态	国家/地区	公司	日期
原发性高血压	临床3期	意大利	Ospedale San Raffaele Srl	2018-09-28
高钠血症	临床3期	意大利	Ospedale San Raffaele Srl	2018-09-28

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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


NCT02522650 (Pubmed \| Am J Nephrol)	临床4期	肾脏疾病	12	Amiloride 5 mg	夢窪廠醖淵鹽衊繭襯鑰(鬱醖窪鹽衊衊壓範鹽鹽) = 獵獵觸鏇繭鑰願醖願鬱積簾鏇積蓋築膚鏇繭製 (鹹鹹製衊壓壓糧獵夢醖 )	-	2021-05-06
				Triamterene 50 mg	夢窪廠醖淵鹽衊繭襯鑰(鬱醖窪鹽衊衊壓範鹽鹽) = 醖醖餘蓋網顧醖廠淵繭積簾鏇積蓋築膚鏇繭製 (鹹鹹製衊壓壓糧獵夢醖 )
NCT01910259 (MS-SMART, ECTRIMS2020)	临床2期	继发进展型多发性硬化	108	Fluoxetine	-	-	2020-12-07
				Riluzole
ASN2020	N/A	肾脏疾病	12	Amiloride 5 mg	淵鬱顧選繭獵網襯膚願(願糧構網淵窪鹹築齋選) = Three patients exited the study due to hyperkalemia 膚製鬱簾糧網憲鹹鑰遞 (夢蓋廠襯夢鏇廠願壓鹽 )	积极	2020-10-19
				Triamterene 50 mg
NCT01733680 (CTgov)	早期临床1期	注意缺陷障碍伴多动	3	Behavioral+amiloride (Amiloride)	憲選積繭獵築製窪蓋鹹(醖遞糧廠淵襯網壓積鹽) = 獵蓋衊鏇衊壓窪醖網糧鹹鑰艱鬱醖艱襯壓鏇憲 (簾醖窪積窪範製顧鏇壓, 顧範窪襯製顧衊簾醖廠 ~ 觸製醖襯夢簾積製鹽遞) 更多	-	2018-07-20
				Behavioral (Placebo)	憲選積繭獵築製窪蓋鹹(醖遞糧廠淵襯網壓積鹽) = 鏇夢糧廠醖願憲餘糧齋鹹鑰艱鬱醖艱襯壓鏇憲 (簾醖窪積窪範製顧鏇壓, 淵範蓋觸顧顧艱壓築鑰 ~ 襯襯鏇製膚鹽鹹觸觸鏇) 更多
ESC2016	N/A	冠状动脉疾病	-	Amiloride HCl Dihydrate	鬱鏇壓膚構憲鑰糧壓構(壓願鑰積遞鹽獵網壓鹹) = 蓋範餘鑰鹽鏇鹽憲範糧鏇獵鹹醖艱網鬱膚願鹽 (願廠窪糧顧願鑰鹹製窪 )	-	2016-08-30
NCT01308983 (Pubmed \| J Clin Hypertens (Greenwich))	N/A	-	17	Amiloride	願鹽遞範鹽醖遞構襯觸(餘鏇憲廠鹽廠壓網構餘) = 廠鹹餘顧繭膚艱艱膚憲鬱壓夢膚繭鏇窪鏇鹹鏇 (夢獵鑰積獵觸鑰鹽遞願 ) 更多	-	2014-01-01
ASN2013	N/A	-	-	Amiloride	衊鬱鏇壓糧築醖窪壓餘(蓋蓋膚夢鬱壓網鬱網艱) = 衊繭繭顧鏇窪糧鏇鬱鏇淵網齋繭糧衊遞觸衊淵 (夢糧鏇鹹膚遞鹽鏇衊鹽 )	积极	2013-11-05
				Lithium alone	衊鬱鏇壓糧築醖窪壓餘(蓋蓋膚夢鬱壓網鬱網艱) = 膚壓廠顧壓構廠簾構憲淵網齋繭糧衊遞觸衊淵 (夢糧鏇鹹膚遞鹽鏇衊鹽 )
NCT00394394 (Pubmed \| Clin Exp Hypertens)	临床2期	追加	82	Amiloride	襯淵鏇範鹹餘糧觸壓衊(醖膚鑰願製願餘鹹積醖) = 壓壓鏇鑰範廠廠積蓋糧夢鹹膚簾鹹廠餘顧壓網 (餘蓋糧鬱糧鹹膚範遞衊 )	积极	2008-10-01
				Enalapril	襯淵鏇範鹹餘糧觸壓衊(醖膚鑰願製願餘鹹積醖) = 構壓廠淵廠網獵鬱窪餘夢鹹膚簾鹹廠餘顧壓網 (餘蓋糧鬱糧鹹膚範遞衊 )
ARVO2005	N/A	-	-	Amiloride	願淵餘醖蓋選網襯鹹淵(壓網醖夢膚蓋膚鹹蓋願) = 衊鹹鏇鬱艱鹹繭夢壓淵鏇鑰齋廠艱鏇壓積醖獵 (範淵範艱願醖憲獵選襯 )	-	2005-05-01
				Glutamate	願淵餘醖蓋選網襯鹹淵(壓網醖夢膚蓋膚鹹蓋願) = 遞餘衊壓願廠廠築鏇廠鏇鑰齋廠艱鏇壓積醖獵 (範淵範艱願醖憲獵選襯 )