主要研究目的研究空腹和餐后单次口服布美他尼片受试制剂（规格：1mg，新乡市常乐制药有限责任公司生产，浙江和沐康医药科技有限公司提供）与布美他尼片参比制剂（Burinex®，规格：1mg，Karo Pharma AB持证，浙江和沐康医药科技有限公司提供）在中国健康受试者体内的药代动力学行为，评价空腹及餐后口服两种制剂的生物等效性。次要研究目的评价中国健康受试者空腹和餐后单次口服受试制剂（T）布美他尼片和参比制剂（R）布美他尼片（Burinex®）后的安全性。

开始日期2024-02-27

申办/合作机构

浙江和沐康医药科技有限公司

NCT06036914 / Enrolling by invitation临床2期IIT

Ultra High Dose Diuretic Strategy for Management of Acute Decompensated Heart Failure - A Randomized, Double-Blind Pilot Trial

The purpose of this study is to determine the safety and effectiveness of ultrahigh dose diuretics compared to standard dose diuretics over 24 hours in patients with decompensated heart failure.

开始日期2023-11-27

申办/合作机构

Mayo Clinic

NCT06052163 / Recruiting临床2期IIT

Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Tolerability of Bumetanide in Patients With Alzheimer's Disease.

This study aims to investigate bumetanide in patients with biologically confirmed Alzheimer's disease (AD). Bumetanide is a potent diuretic administered orally and is FDA approved for the treatment of edema and hypertension. Repurposing bumetanide as a medication for AD has been proposed based on data that demonstrated its ability to "flip" the APOE genotype-dependent transcriptomic signatures in AD mouse and cell culture models. Critically, this discovery was subsequently explored in Electronic Health Record cohorts, which revealed that among individuals over the age of 65, bumetanide exposure was significantly associated with a lower prevalence of AD in three independent datasets.
Primary Objective: To evaluate the safety and tolerability of bumetanide when administered to participants with biomarker-confirmed Alzheimer's disease.
Secondary Objective: To evaluate the clinical and biomarker effects of bumetanide in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease.

开始日期2023-04-10

申办/合作机构

Stanford University

100 项与 NKCC2 x SLC12A4 x NKCC1 相关的临床结果

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100 项与 NKCC2 x SLC12A4 x NKCC1 相关的转化医学

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0 项与 NKCC2 x SLC12A4 x NKCC1 相关的专利（医药）

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项与 NKCC2 x SLC12A4 x NKCC1 相关的文献（医药）

2023-12-01·Journal of Pharmaceutical Analysis

The role of SLC12A family of cation-chloride cotransporters and drug discovery methodologies

Review

作者: Dai, Cuilian ; Zhou, Xiaoxia ; Li, Zhengqiu ; Liang, Dong ; Wang, Yan ; Meor Azlan, Nur Farah ; Josiah, Sunday Solomon ; Wang, Yun ; Li, Peifeng ; Zhang, Shiyao ; Wang, Zhen ; Zhang, Jinwei ; Ding, Ke ; Jie, Lingjun ; Zhang, Yanhui ; Zhou, Jing

The solute carrier family 12 (SLC12) of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl^- extrusion, and sodium potassium chloride cotransporters (N[K]CCs, NKCC1, NKCC2, and NCC)-mediated Cl^- loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues. In recent years, there have been considerable advances in our understanding of CCCs' control mechanisms in cell volume regulations, with many techniques developed in studying the functions and activities of CCCs. Classic approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the CCCs. These techniques include the ammonium pulse technique, radioactive or nonradioactive rubidium ion uptake-assay, and thallium ion-uptake assay. CCCs' activity can also be indirectly observed by measuring γ-aminobutyric acid (GABA) activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes, radiotracer ³⁶Cl^-, and fluorescent dyes. Other techniques include directly looking at kinase regulatory sites phosphorylation, flame photometry, ²²Na⁺ uptake assay, structural biology, molecular modeling, and high-throughput drug screening. This review summarizes the role of CCCs in genetic disorders and cell volume regulation, current methods applied in studying CCCs biology, and compounds developed that directly or indirectly target the CCCs for disease treatments.

2023-05-01·Acta Histochemica

KCCs, NKCCs, and NCC: Potential targets for cardiovascular therapeutics? A comprehensive review of cell and region specific expression and function

Review

作者: Khan, Areej Naim ; Cheng, Wing Yan Elizabeth ; Modi, Dharmeshkumar M ; Modi, Akshat D

Cardiovascular diseases, the leading life-threatening conditions, involve cardiac arrhythmia, coronary artery disease, myocardial infarction, heart failure, cardiomyopathy, and heart valve disease that are associated with the altered functioning of cation-chloride cotransporters. The decreased number of cation-chloride cotransporters leads to reduced reactivity to adrenergic stimulation. The KCC family is crucial for numerous physiological processes including cell proliferation and invasion, regulation of membrane trafficking, maintaining ionic and osmotic homeostasis, erythrocyte swelling, dendritic spine formation, maturation of postsynaptic GABAergic inhibition, and inhibitory/excitatory signaling in neural tracts. KCC2 maintains intracellular chlorine homeostasis and opposes β-adrenergic stimulation-induced Cl- influx to prevent arrhythmogenesis. KCC3-inactivated cardiac tissue shows increased vascular resistance, aortic distensibility, heart size and weight (i.e. hypertrophic cardiomyopathy). Due to KCC4's high affinity for K+, it plays a vital role in cardiac ischemia with increased extracellular K+. The NKCC and NCC families play a vital role in the regulation of saliva volume, establishing the potassium-rich endolymph in the cochlea, sodium uptake in astrocytes, inhibiting myogenic response in microcirculatory beds, regulation of smooth muscle tone in resistance vessels, and blood pressure. NKCC1 regulates chlorine homeostasis and knocking it out impairs cardiomyocyte depolarization and cardiac contractility as well as impairs depolarization and contractility of vascular smooth muscle rings in the aorta. The activation of NCC in vascular cells promotes the formation of the abdominal aortic aneurysm. This narrative review provides a deep insight into the structure and function of KCCs, NKCCs, and NCC in human physiology and cardiac pathobiology. Also, it provides cell-specific (21 cell types) and region-specific (6 regions) expression of KCC1, KCC2, KCC3, KCC4, NKCC1, NKCC2, and NCC in heart.

2020-08-01·Hearing Research1区 · 医学

Expression patterns of chloride transporters in the auditory brainstem of developing chicken

1区 · 医学

Article

作者: Kriebel, Andreas ; Wirth, Marcus J ; Mey, Jörg ; Ackels, Tobias ; Wagner, Hermann ; Kuenzel, Thomas ; Kriebel, Katharina

GABAergic transmission changes from depolarization to hyperpolarization in most vertebrate brain regions during development. By contrast, in the auditory brainstem of chicken a depolarizing effect of GABA persists after hatching. Since auditory brainstem neurons that receive GABAergic input have a Cl^- reversal potential above resting membrane potential, a specifically tuned activity of Cl^- transporters is likely. We here present a developmental study of the expression patterns of several members of the SLC12 family (NKCC1, NKCC2, KCC1, KCC2, KCC4, CCC6, CCC9) and of AE3 at developmental ages E7, E10, E12, E15, E17, and P1 with quantitative RT-PCR. NKCC2 and CCC9 were not detected in auditory brainstem (positive control: kidney). KCC1, CCC6 and AE3 were expressed, but not regulated, while NKCC1, KCC2 and KCC4 were regulated. The expression of the latter transporters increased, with KCC2 exhibiting the strongest expression at all time points. Biochemical analysis of the protein expression of NKCC1, KCC2 and KCC4 corroborated the findings on the mRNA level. All three transporters showed a localization at the outer rim of the cells, with NKCC1 and KCC2 expressed in neurons, and KCC4 predominantly in glia. The comparison of the published chloride reversal potential and expression of transporter proteins suggest strong differences in the efficiency of the three transporters. Further, the strong KCC2 expression could reflect a role in the structural development of auditory brainstem synapses that might lead to changes in the physiological properties.