Torsemide vs. Furosemide for Edema Control in Children with Nephrotic Syndrome Relapses: A Single Blinded Non-Inferiority Randomized Control Trial - Nil

Start Date16 Sep 2024

Sponsor / Collaborator-

NCT06176794 / RecruitingPhase 2

A Crossover Study of Patients With Heart Failure to Compare Natriuretic Effects of Immediate Release Torsemide vs. Extended Release Torsemide Over 12 Hours After Dosing

The goal of this randomized double-blind crossover study is to assess whether a morning dose of the extended release torsemide has a better efficacy than the ordinary immediate release torsemide to induce renal sodium excretion after a salty lunch in patients with stable heart failure. The main questions it aims to answer are:
* Are the amounts of excreted sodium in the urine during the 2- and 6-hours' time period after a morning dose of extended release torsemide different from the amounts after the immediate release torsemide.
* Are the amounts of excreted sodium in the urine during the 2- and 6-hours' time period after a salty lunch, which will be consumed approximately 6 hours following a morning dose of extended release torsemide, different from the amounts after the immediate release torsemide.
* Is the amount of excreted sodium in the urine during the 24 hours' time period after a salty lunch, which will be consumed approximately 6 hours following a morning dose of extended release torsemide, different from the amount after the immediate release torsemide.
Participants will be asked to:
* Start taking daily immediate release or extended release torsemide tablets that is provided to them.
* Eat the meals with standard contents of sodium that is provided to them and avoid other meals, drinks (except for water) and snacks for the duration of the study.
* Collect urine for 24 hours, after approximately one week of the initiation of the study medication.
* Go to the clinical research center the day that the 24-hour urine collection is finished and stay there throughout the day to receive standard meals and to have blood and urine samples collected.
* Switch torsemide pills to the new one that will be dispensed to them at the clinical research center. If they were taking the immediate release torsemide during the first part, then they will be given the sustained release torsemide and vice versa. The study is double blind; therefore, the subjects, study coordinators, and investigators are unaware of whether each subject is on immediate release torsemide first or on extended release torsemide first.
* Collect urine for an additional 12 hours after leaving the clinical research center to be sent to the clinical research center the next morning.
* Continue to take the provided meals and to avoid other meals, drinks (except for water) and snacks.
* Again, collect urine for 24 hours, after approximately one week, take that to the clinical research center when the 24-hour collection is completed and stay there throughout the day to receive standard meals and to have blood and urine samples collected.
* Collect urine for an additional 12 hours to be sent to the clinical research center the next morning.
Researchers will compare the amount of sodium excretion when each subject is taking immediate release torsemide versus the time that the same subject is taking extended release torsemide.

Start Date01 Jul 2024

Sponsor / Collaborator

Sarfez Pharmaceuticals, Inc.

NCT06206512 / RecruitingPhase 2

A Crossover, Double-blinded, Two-period, Double Dummy Study to Evaluate the Effects of Extended Release Torsemide in Patients With Chronic Congestive Heart Failure and Symptoms of Overactive Bladder

This research study is being done to compare the effectiveness two drugs: an extended release torsemide (ERT) versus generic immediate release Torsemide (IRT) in reducing the worsening of symptoms of Overactive Bladder (OAB i.e., frequency, urgency, or urgency incontinence) in patients with chronic congestive heart failure (CHF).
This study will include CHF patients who experience worsening OAB) symptoms with use of a loop diuretic. The total duration of the study is about eight weeks with a total of nine visits.
There will be a screening visit that lasts one to two hours. The screening visit includes history and physical exams, blood draws, and urine analysis. If eligible for the study, participants will receive either generic torsemide or extended release torsemide for the first four weeks. Participants will do a virtual research visit on week one, two and three to submit a symptom diary and answer a questionnaire about urinary symptoms. At four weeks, history and physician exam will be done and blood will be collected. Participants will be assigned to receive either extended release torsemide (if they initially received generic torsemide) and generic torsemide (if they initially received extended release torsemide) for the next four weeks. Participants will attend virtual research visits on week five, six and seven to submit a symptom diary and answer a questionnaire about urinary symptoms. At the end of the study in week eight, they will have history and physical exams and blood draws.
Some risks from the study may include side effects of torsemide like acute kidney injury, fluid/electrolyte loss, hypersensitivity reactions and reversible hearing loss/tinnitus.

Start Date01 Jun 2024

Sponsor / Collaborator

Sarfez Pharmaceuticals, Inc.

100 Clinical Results associated with NKCC2 x NKCC1

100 Translational Medicine associated with NKCC2 x NKCC1

0 Patents (Medical) associated with NKCC2 x NKCC1

143

Literatures (Medical) associated with NKCC2 x NKCC1

01 Sep 2024·CNS Neuroscience & Therapeutics

Combined use of CLP290 and bumetanide alleviates neuropathic pain and its mechanism after spinal cord injury in rats

Article

Author: Talifu, Zuliyaer ; Yu, Yan ; Pan, Yun‐zhu ; Ke, Han ; Li, Jian‐Jun ; Du, Liang‐jie ; Zhang, Chun‐jia ; Wang, Xiao‐xin ; Xu, Xin ; Gao, Feng ; Yang, De‐gang

AbstractAimWe aimed to explore whether the combination of CLP290 and bumetanide maximally improves neuropathic pain following spinal cord injury (SCI) and its possible molecular mechanism.MethodsRats were randomly divided into five groups: Sham, SCI + vehicle, SCI + CLP290, SCI + bumetanide, and SCI + combination (CLP290 + bumetanide). Drug administration commenced on the 7th day post‐injury (7 dpi) and continued for 14 days. All rats underwent behavioral assessments for 56 days to comprehensively evaluate the effects of interventions on mechanical pain, thermal pain, cold pain, motor function, and other relevant parameters. Electrophysiological assessments, immunoblotting, and immunofluorescence detection were performed at different timepoints post‐injury, with a specific focus on the expression and changes of KCC2 and NKCC1 proteins in the lumbar enlargement of the spinal cord.ResultsCLP290 and bumetanide alleviated SCI‐associated hypersensitivity and locomotor function, with the combination providing enhanced recovery. The combined treatment group exhibited the most significant improvement in restoring Rate‐Dependent Depression (RDD) levels. In the combined treatment group and the two individual drug administration groups, the upregulation of potassium chloride cotransporter 2 (K+‐Cl−cotransporter 2, KCC2) expression and downregulation of sodium potassium chloride cotransporter 1 (Na+‐K+‐Cl−cotransporter 1, NKCC1) expression in the lumbar enlargement area resulted in a significant increase in the KCC2/NKCC1 ratio compared to the SCI + vehicle group, with the most pronounced improvement seen in the combined treatment group. Compared to the SCI + vehicle group, the SCI + bumetanide group showed no significant paw withdrawal thermal latency (PWTL) improvement at 21 and 35 dpi, but a notable enhancement at 56 dpi. In contrast, the SCI + CLP290 group significantly improved PWTL at 21 days, with non‐significant changes at 35 and 56 days. At 21 dpi, KCC2 expression was marginally higher in monotherapy groups versus SCI + vehicle, but not significantly. At 56 dpi, only the SCI + bumetanide group showed a significant difference in KCC2 expression compared to the control group.ConclusionCombined application of CLP290 and bumetanide effectively increases the ratio of KCC2/NKCC1, restores RDD levels, enhances GABAA receptor‐mediated inhibitory function in the spinal cord, and relieves neuropathic pain in SCI; Bumetanide significantly improves neuropathic pain in the long term, whereas CLP290 demonstrates a notable short‐term effect.

03 Jun 2024·Brain

Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer’s disease and 5XFAD mice

Article

Author: Talos, Delia M ; Irwin, David J ; Gourmaud, Sarah ; Barbour, Aaron J ; Li, Xiaofan ; Jensen, Frances E ; Hoag, Keegan F ; Lancaster, Eunjoo ; Stewart, David A

AbstractApproximately 22% of Alzheimer’s disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbates AD pathology and related cognitive deficits, suggesting that seizures may be a targetable component of AD progression. Given that alterations in neuronal excitatory:inhibitory (E:I) balance occur in epilepsy, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients. We similarly hypothesized that in 5XFAD mice, the E:I imbalance would progress from an early stage (prodromal) to later symptomatic stages and be further exacerbated by pentylenetetrazol (PTZ) kindling.Post-mortem AD temporal cortical tissues from patients with or without seizure history were examined for changes in several markers of E:I balance, including levels of the inhibitory GABAA receptor, the sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2) and the excitatory NMDA and AMPA type glutamate receptors. We performed patch-clamp electrophysiological recordings from CA1 neurons in hippocampal slices and examined the same markers of E:I balance in prodromal 5XFAD mice. We next examined 5XFAD mice at chronic stages, after PTZ or control protocols, and in response to chronic mTORC1 inhibitor rapamycin, administered following kindled seizures, for markers of E:I balance.We found that AD patients with comorbid seizures had worsened cognitive and functional scores and decreased GABAA receptor subunit expression, as well as increased NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. Patch clamp recordings of prodromal 5XFAD CA1 neurons showed increased intrinsic excitability, along with decreased GABAergic inhibitory transmission and altered glutamatergic neurotransmission, indicating that E:I imbalance may occur in early disease stages. Furthermore, seizure induction in prodromal 5XFAD mice led to later dysregulation of NKCC1/KCC2 and a reduction in GluA2 AMPA glutamate receptor subunit expression, indicative of depolarizing GABA receptors and calcium permeable AMPA receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced amyloid-β pathology and cognitive deficits, could also reverse elevations of the NKCC1/KCC2 ratio in these mice.Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that targeting E:I balance, potentially with US Food and Drug Administration-approved mTOR inhibitors, hold therapeutic promise for AD patients with a seizure history.

01 Mar 2024·Journal of Cell Science

The epithelial polarity axis controls the resting membrane potential and Cl− co-transport in breast glandular structures

Article

Author: Lelièvre, Sophie A ; Urazaev, Albert K ; Wang, Lei ; Bai, Yunfeng ; Adissu, Hibret A

ABSTRACTThe membrane potential (MP) controls cell homeostasis by directing molecule transport and gene expression. How the MP is set upon epithelial differentiation is unknown. Given that tissue architecture also controls homeostasis, we investigated the relationship between basoapical polarity and resting MP in three-dimensional culture of the HMT-3522 breast cancer progression. A microelectrode technique to measure MP and input resistance reveals that the MP is raised by gap junction intercellular communication (GJIC), which directs tight-junction mediated apical polarity, and is decreased by the Na+/K+/2Cl− (NKCC, encoded by SLC12A1 and SLC12A2) co-transporter, active in multicellular structures displaying basal polarity. In the tumor counterpart, the MP is reduced. Cancer cells display diminished GJIC and do not respond to furosemide, implying loss of NKCC activity. Induced differentiation of cancer cells into basally polarized multicellular structures restores widespread GJIC and NKCC responses, but these structures display the lowest MP. The absence of apical polarity, necessary for cancer onset, in the non-neoplastic epithelium is also associated with the lowest MP under active Cl− transport. We propose that the loss of apical polarity in the breast epithelium destabilizes cellular homeostasis in part by lowering the MP.

News (Medical) associated with NKCC2 x NKCC1

25 Jul 2022

·www.biospace.com

IAMA Therapeutics Announces Initiation of Preclinical Development Studies in Drug-resistant Epilepsy Under a Service Agreement with Psychogenics

July 25, 2022 12:00 UTC GENOA, Italy--(BUSINESS WIRE)-- IAMA Therapeutics, a preclinical-stage pharmaceutical company focused on the discovery, development, and commercialization of novel medicines to make a difference in the lives of individuals suffering from brain disorders, and PsychoGenics Inc. Inc., a leader in AI-enabled phenotypic drug discovery and preclinical CRO services, today announced that the companies have entered into a service agreement to identify the efficacy of novel drug candidates in drug-resistant epilepsy. Under the terms of the agreement, PsychoGenics will evaluate the preclinical anti-seizure efficacy of first-in-class selective-NKCC1 inhibitors, which aims to reduce intracellular chloride concentration and restore the physiological hyperpolarizing and inhibitory GABAergic transmission in an animal model of refractory epilepsy. "PsychoGenics is a leader in preclinical behavioral neurobiology with a successful track record of anti-epilepsy drug testing through translational EEG approaches, including electrographic and behavioral identification of seizure," said Andrea P. Malizia, Ph.D., MBA, Chief Executive Officer of IAMA Therapeutics. "We look forward to leveraging our collective expertise in neuroscience drug development to identify and evaluate the anti-seizure efficacy of new drug candidates, to enhance further and complement our pipeline of differentiated therapeutic opportunities for epilepsy, neurodevelopmental and cognitive disorders." “We are excited to embark of these studies with IAMA Therapeutics” said Stephen Morairty, Ph.D., Vice President of Translational Neuroscience at PsychoGenics. “Using our pre-clinical MTLE model, will carefully evaluate the efficacy of these first-in-class selective-NKCC1 inhibitors.” About IAMA Therapeutics IAMA Therapeutics is a preclinical-stage pharmaceutical company focused on discovering, developing, and commercializing novel medicines to make a difference in the lives of children and adults suffering from epilepsy, neurodevelopmental and cognitive disorders. IAMA Therapeutics couples emerging advances in drug discovery and neurobiology to build a leading, next-generation neuroscience pipeline to selectively inhibit the sodium-potassium chloride cotransporter and other therapeutic targets relevant to brain disorders characterized by neuronal imbalance. The company's preclinical pipeline consists of the lead candidate IAMA-6 for the treatment of idiopathic autism, IAMA-097 for the treatment of secondary and rare forms of autism, and other compounds for treating refractory epilepsy and other brain disorders. For more information, please visit About PsychoGenics Inc. PsychoGenics is a leader in vivo phenotypic drug discovery. The company applies its proprietary technology platforms in partnership with pharmaceutical and biotechnology companies to discover the next generation of drugs for neuropsychiatric disorders. PsychoGenics' capabilities include standard behavioral testing, electrophysiology, translational EEG, molecular biology, and state-of-the-art microdialysis. In addition, the company offers a variety of in-licensed transgenic mouse models that support research in areas such as Huntington's disease, Autism spectrum disorders, psychosis/schizophrenia, Alzheimer's disease, Parkinson's disease, sleep, and Spinal Muscular Atrophy (SMA), muscular dystrophy and other muscle disorders. For more information on PsychoGenics Inc., visit .

CollaborateFirst in Class

29 Jun 2022

·www.biospace.com

IAMA Therapeutics to Present Preclinical Data of Selective NKCC1-Inhibitors at the International Neuroscience Conference FENS Forum 2022

GENOA, Italy--(BUSINESS WIRE)-- IAMA Therapeutics, a preclinical-stage pharmaceutical company focused on the discovery, development, and commercialization of novel medicines to make a difference in the lives of individuals suffering from brain disorders, announced today it will present a poster at the upcoming International Neuroscience Conference of the Federation of the European Neuroscience Societies (FENS). The conference will take place in Paris, France, from July 9-13, 2022. “We are excited to release preclinical data for selective NKCC1-inhibitors from our neuroscience drug discovery initiative, which we believe has the potential to fundamentally redefine the therapeutic opportunities for children and adults with neurodevelopmental and cognitive disorders. These results demonstrated that our candidates led to meaningful and durable responses in animal models of Down syndrome and autism spectrum disorders with no apparent observed toxicity,” said Andrea P. Malizia, PhD, MBA, Chief Executive Officer of IAMA Therapeutics. Details of the poster presentation are as follows: Title: Selective NKCC1 inhibitors for the treatment of Autism, Down syndrome, and brain disorders with defective neuronal Cl homeostasis. Presenter: Annalisa Savardi PhD, Team Leader in Neuropharmacology, IAMA Therapeutics. Poster Session: 03 Board Number: S03-386 Session Date and Time: Monday, July 11, 2022, 09:30 AM-1:00 PM (CET) About IAMA-6 IAMA-6 is a first-in-class selective-NKCC1 inhibitor that modulates the intracellular chloride, reducing the depolarizing strength of GABAA receptors to the levels required to restore the inhibitory transmission. This pathway is reported in Down syndrome, autism spectrum disorder, epilepsy, and other brain disorders characterized by increased intracellular chloride and depolarizing GABAergic transmission. About IAMA Therapeutics IAMA Therapeutics is a preclinical-stage pharmaceutical company focused on discovering, developing, and commercializing novel medicines to make a difference in the lives of children and adults suffering from neurodevelopmental and cognitive disorders. IAMA Therapeutics couples emerging advances in drug discovery and neurobiology to build a leading, next-generation neuroscience pipeline to selectively inhibit the sodium-potassium chloride cotransporter and other therapeutic targets relevant to brain disorders characterized by neuronal imbalance. The company’s preclinical pipeline consists of the lead candidate IAMA-6 for the treatment of idiopathic autism, IAMA-097 for the treatment of secondary and rare forms of autism, and other compounds for the treatment of refractory epilepsy and other brain disorders.

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