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European Journal of Heart Failure Nov 2019To investigate the effects of acetazolamide on natriuresis, decongestion, kidney function and neurohumoral activation in acute heart failure (AHF). (Comparative Study)
Comparative Study Randomized Controlled Trial
AIMS
To investigate the effects of acetazolamide on natriuresis, decongestion, kidney function and neurohumoral activation in acute heart failure (AHF).
METHODS AND RESULTS
This prospective, two-centre study included 34 AHF patients on loop diuretics with volume overload. All had a serum sodium concentration < 135 mmol/L and/or serum urea/creatinine ratio > 50 and/or an admission serum creatinine increase of > 0.3 mg/dL compared to baseline. Patients were randomised towards acetazolamide 250-500 mg daily plus bumetanide 1-2 mg bid vs. high-dose loop diuretics (bumetanide bid with daily dose twice the oral maintenance dose). The primary endpoint was natriuresis after 24 h. Natriuresis after 24 h was similar in the combinational treatment vs. loop diuretic only arm (264 ± 126 vs. 234 ± 133 mmol; P = 0.515). Loop diuretic efficiency, defined as natriuresis corrected for loop diuretic dose, was higher in the group receiving acetazolamide (84 ± 46 vs. 52 ± 42 mmol/mg bumetanide; P = 0.048). More patients in the combinational treatment arm had an increase in serum creatinine levels > 0.3 mg/dL (P = 0.046). N-terminal pro-B-type natriuretic peptide reduction and peak neurohumoral activation within 72 h were comparable among treatment arms. There was a non-significant trend towards lower all-cause mortality or heart failure readmissions in the group receiving acetazolamide with low-dose loop diuretics vs. high-dose loop diuretic monotherapy (P = 0.098).
CONCLUSION
Addition of acetazolamide increases the natriuretic response to loop diuretics compared to an increase in loop diuretic dose in AHF at high risk for diuretic resistance.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01973335.
Topics: Acetazolamide; Adult; Aged; Bumetanide; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Female; Heart Failure; Humans; Kidney Function Tests; Male; Middle Aged; Natriuresis; Prospective Studies; Risk Factors; Sodium Potassium Chloride Symporter Inhibitors; Survival Analysis
PubMed: 31074184
DOI: 10.1002/ejhf.1478 -
BMJ Case Reports Feb 2020A 62-year-old woman with chronic kidney disease stage 4, sleep apnoea on continuous positive airway pressure and recent admission for acute-on-chronic diastolic heart...
A 62-year-old woman with chronic kidney disease stage 4, sleep apnoea on continuous positive airway pressure and recent admission for acute-on-chronic diastolic heart failure presented to emergency room with weakness. She was hypotensive and had symptomatic bradycardia in the 30 s secondary to hyperkalaemia and beta-blockers, raising concern for BRASH syndrome. Antihypertensives were immediately held. Potassium-lowering agents (with calcium gluconate for cardiac stability) were begun, as were fluids and dopamine for vasopressor support. The patient was admitted to intensive care unit and electrophysiology was consulted. Over the next 2 days, the patient clinically improved: she remained off dopamine for over 24 hours; potassium levels and renal function improved; and heart rate stabilised in 60 s. The patient was eventually discharged and advised to avoid metolazone, bumetanide and carvedilol, with primary care provider and cardiology follow-up.
Topics: Antihypertensive Agents; Atrioventricular Block; Bradycardia; Bumetanide; Carvedilol; Female; Humans; Hyperkalemia; Metolazone; Middle Aged; Renal Insufficiency; Shock; Syndrome; Vasoconstrictor Agents
PubMed: 32094236
DOI: 10.1136/bcr-2019-233825 -
Neuropharmacology Mar 2022The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl cotransporter KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation... (Review)
Review
The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl cotransporter KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation and consequent effects on GABAergic signaling have been implicated in numerous CNS disorders. While KCC2 modulators are not yet clinically available, the loop diuretic bumetanide has been used in clinical studies to treat brain disorders and as a tool for NKCC1 inhibition in preclinical models. Bumetanide is known to have anticonvulsant and neuroprotective effects under some pathophysiological conditions. However, as shown in several species from neonates to adults (mice, rats, dogs, and by extrapolation in humans), at the low clinical doses of bumetanide approved for diuresis, this drug has negligible access into the CNS, reaching levels that are much lower than what is needed to inhibit NKCC1 in cells within the brain parenchyma. Several drug discovery strategies have been used over the last ∼15 years to develop brain-permeant compounds that, ideally, should be selective for NKCC1 to eliminate the diuresis mediated by inhibition of renal NKCC2. The strategies employed to improve the pharmacokinetic and pharmacodynamic properties of NKCC1 blockers include evaluation of other clinically approved loop diuretics; development of lipophilic prodrugs of bumetanide; development of side-chain derivatives of bumetanide; and unbiased high-throughput screening approaches of drug discovery based on large chemical compound libraries. The main outcomes are that (1), non-acidic loop diuretics such as azosemide and torasemide may have advantages as NKCC1 inhibitors vs. bumetanide; (2), bumetanide prodrugs achieve significantly higher brain levels of the parent drug and have lower diuretic activity; (3), the novel bumetanide side-chain derivatives do not exhibit any functionally relevant improvement of CNS accessibility or NKCC1 selectivity vs. bumetanide; (4) novel compounds discovered by high-throughput screening may resolve some of the inherent problems of bumetanide, but as yet this has not been achieved. Thus, further research is needed to optimize the design of brain-permeant NKCC1 inhibitors. Another major challenge is to identify the mechanisms whereby various NKCC1-expressing cellular targets of these drug within (e.g., neurons, oligodendrocytes or astrocytes) and outside the brain parenchyma (e.g., blood-brain barrier, choroid plexus, endocrine and immune system), as well as molecular off-target effects, might contribute to their reported therapeutic and adverse effects.
Topics: Animals; Bumetanide; Central Nervous System; Humans; Sodium Potassium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 2
PubMed: 34883135
DOI: 10.1016/j.neuropharm.2021.108910 -
Brain : a Journal of Neurology Oct 2023Although the Na-K-Cl cotransporter (NKCC1) inhibitor bumetanide has prominent positive effects on the pathophysiology of many neurological disorders, the mechanism of...
Although the Na-K-Cl cotransporter (NKCC1) inhibitor bumetanide has prominent positive effects on the pathophysiology of many neurological disorders, the mechanism of action is obscure. Attention paid to elucidating the role of Nkcc1 has mainly been focused on neurons, but recent single cell mRNA sequencing analysis has demonstrated that the major cellular populations expressing NKCC1 in the cortex are non-neuronal. We used a combination of conditional transgenic animals, in vivo electrophysiology, two-photon imaging, cognitive behavioural tests and flow cytometry to investigate the role of Nkcc1 inhibition by bumetanide in a mouse model of controlled cortical impact (CCI). Here, we found that bumetanide rescues parvalbumin-positive interneurons by increasing interneuron-microglia contacts shortly after injury. The longitudinal phenotypic changes in microglia were significantly modified by bumetanide, including an increase in the expression of microglial-derived BDNF. These effects were accompanied by the prevention of CCI-induced decrease in hippocampal neurogenesis. Treatment with bumetanide during the first week post-CCI resulted in significant recovery of working and episodic memory as well as changes in theta band oscillations 1 month later. These results disclose a novel mechanism for the neuroprotective action of bumetanide mediated by an acceleration of microglial activation dynamics that leads to an increase in parvalbumin interneuron survival following CCI, possibly resulting from increased microglial BDNF expression and contact with interneurons. Salvage of interneurons may normalize ambient GABA, resulting in the preservation of adult neurogenesis processes as well as contributing to bumetanide-mediated improvement of cognitive performance.
Topics: Mice; Animals; Bumetanide; Sodium Potassium Chloride Symporter Inhibitors; Microglia; Brain-Derived Neurotrophic Factor; Parvalbumins; Solute Carrier Family 12, Member 2; Interneurons; Neurogenesis
PubMed: 37082944
DOI: 10.1093/brain/awad132 -
Cells Jan 2022GABA depolarizes and often excites immature neurons in all animal species and brain structures investigated due to a developmentally regulated reduction in intracellular... (Review)
Review
GABA depolarizes and often excites immature neurons in all animal species and brain structures investigated due to a developmentally regulated reduction in intracellular chloride concentration ([Cl]) levels. The control of [Cl] levels is mediated by the chloride cotransporters NKCC1 and KCC2, the former usually importing chloride and the latter exporting it. The GABA polarity shift has been extensively validated in several experimental conditions using often the NKCC1 chloride importer antagonist bumetanide. In spite of an intrinsic heterogeneity, this shift is abolished in many experimental conditions associated with developmental disorders including autism, Rett syndrome, fragile X syndrome, or maternal immune activation. Using bumetanide, an EMA- and FDA-approved agent, many clinical trials have shown promising results with the expected side effects. Kaila et al. have repeatedly challenged these experimental and clinical observations. Here, we reply to the recent reviews by Kaila et al. stressing that the GABA polarity shift is solidly accepted by the scientific community as a major discovery to understand brain development and that bumetanide has shown promising effects in clinical trials.
Topics: Animals; Autistic Disorder; Brain; Bumetanide; Chlorides; gamma-Aminobutyric Acid
PubMed: 35159205
DOI: 10.3390/cells11030396 -
Trends in Pharmacological Sciences Dec 2021The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. A defective NKCC1/KCC2 expression ratio is associated... (Review)
Review
The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. A defective NKCC1/KCC2 expression ratio is associated with several brain disorders. Preclinical/clinical studies have shown that NKCC1 inhibition by the United States FDA-approved diuretic bumetanide is a potential therapeutic strategy in preclinical/clinical studies of multiple neurological conditions. However, bumetanide has poor brain penetration and causes unwanted diuresis by inhibiting NKCC2 in the kidney. To overcome these issues, a growing number of studies have reported more brain-penetrating and/or selective bumetanide prodrugs, analogs, and new molecular entities. Here, we review the evidence for NKCC1 pharmacological inhibition as an effective strategy to manage neurological disorders. We also discuss the advantages and limitations of bumetanide repurposing and the benefits and risks of new NKCC1 inhibitors as therapeutic agents for brain disorders.
Topics: Brain Diseases; Bumetanide; Chlorides; Humans; Nervous System Diseases; Sodium Potassium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 2
PubMed: 34620512
DOI: 10.1016/j.tips.2021.09.005 -
Nature Aging Oct 2021The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational...
The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aβ accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.
Topics: Mice; Humans; Animals; Alzheimer Disease; Apolipoprotein E4; Bumetanide; Amyloid beta-Peptides; Drug Repositioning; Mice, Transgenic; Apolipoproteins E
PubMed: 36172600
DOI: 10.1038/s43587-021-00122-7 -
Epilepsia Jun 2014Seizures are a common manifestation of acute neurologic insults in neonates and are often resistant to the standard antiepileptic drugs that are efficacious in children... (Review)
Review
Seizures are a common manifestation of acute neurologic insults in neonates and are often resistant to the standard antiepileptic drugs that are efficacious in children and adults. The paucity of evidence-based treatment guidelines, coupled with a rudimentary understanding of disease pathogenesis, has made the current treatment of neonatal seizures empiric and often ineffective, highlighting the need for novel therapies. Key developmental differences in γ-aminobutyric acid (GABA)ergic neurotransmission between the immature and mature brain, and trauma-induced alterations in the function of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although CCCs are attractive drug targets, bumetanide and other existing CCC inhibitors are suboptimal because of pharmacokinetic constraints and lack of target specificity. Newer approaches including isoform-specific NKCC1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC2-mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABAergic system for neonatal seizure treatment. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Topics: Anticonvulsants; Brain; Bumetanide; Humans; Infant, Newborn; Infant, Newborn, Diseases; Seizures; Sodium-Potassium-Chloride Symporters; Solute Carrier Family 12, Member 2; Symporters; K Cl- Cotransporters
PubMed: 24802699
DOI: 10.1111/epi.12620 -
Acta Paediatrica (Oslo, Norway : 1992) May 2021Bumetanide, a diuretic agent, that reduces intracellular chloride-thereby reinforcing GABAergic inhibition-has been reported to improve core symptoms of autism in...
AIM
Bumetanide, a diuretic agent, that reduces intracellular chloride-thereby reinforcing GABAergic inhibition-has been reported to improve core symptoms of autism in children. Given the positive results reported from French trials of bumetanide in children with autism, we decided to evaluate its effects in a small-scale pilot study, in advance of a larger randomised controlled study (RCT).
METHODS
This was an open-label three-month trial of bumetanide on six children (five boys), aged 3-14 years with autism. Ratings according to the Parental Satisfaction Survey (PASS) were used after four and twelve weeks to assess symptom change. Blood electrolyte status was monitored.
RESULTS
Improvement in the PASS domain "Communicative and cognitive abilities" was marked or very marked in four children, and two had some improvements. Few negative side effects were reported.
CONCLUSION
Our small cohort responded well to bumetanide, particularly with regard to "Communicative and cognitive abilities". Taken with the evidence from larger-scale RCTs, we suggest that bumetanide should be considered for inclusion in ethically approved treatment/management trials for children with autism, subject to rigorous follow-up in large-scale RCTs.
Topics: Adolescent; Autistic Disorder; Bumetanide; Child; Child, Preschool; Humans; Male; Parents; Pilot Projects
PubMed: 33336381
DOI: 10.1111/apa.15723 -
Epilepsia Jul 2022A recent Phase II randomized, controlled trial of bumetanide as an adjunctive treatment for neonatal seizures showed a robust efficacy signal and no evidence of... (Randomized Controlled Trial)
Randomized Controlled Trial
A recent Phase II randomized, controlled trial of bumetanide as an adjunctive treatment for neonatal seizures showed a robust efficacy signal and no evidence of toxicity. Concerns regarding bumetanide as an adjunctive anticonvulsant are addressed here. An adequately powered multi-institutional trial is needed to accurately determine efficacy.
Topics: Bumetanide; Epilepsy; Humans; Infant, Newborn; Infant, Newborn, Diseases; Seizures; Sodium Potassium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 2
PubMed: 35524444
DOI: 10.1111/epi.17278