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Restorative Neurology and Neuroscience 2019Stroke often leads to neuronal injury and neurological functional deficits. Whilst spontaneous neurogenesis and axon regeneration are induced by ischemic stroke,... (Review)
Review
Stroke often leads to neuronal injury and neurological functional deficits. Whilst spontaneous neurogenesis and axon regeneration are induced by ischemic stroke, effective pharmacological treatments are also essential for the improvement of neuroplasticity and functional recovery after stroke. However, no pharmacological therapy has been demonstrated to be able to effectively improve the functional recovery after stroke. Bumetanide is a specific Na+-K+-Cl- co-transporter inhibitor which can maintain chloride homeostasis in neurons. Therefore, many studies have focused on this drug's effect in stroke recovery in recent years. Here, we first review the function of Na+-K+-Cl- co-transporter in neurons, then how bumetanide's role in reducing brain damage, promoting neuroplasticity, leading to functional recovery after stroke, is elucidated. Finally, we discuss current limitations of bumetanide's efficiency and their potential solutions. These results may provide new avenues for further exploring mechanisms of post-stroke functional recovery as well as promising therapeutic targets for functional disability rehabilitation after ischemic stroke.
Topics: Animals; Bumetanide; Humans; Neuronal Plasticity; Neurons; Recovery of Function; Sodium Potassium Chloride Symporter Inhibitors; Stroke
PubMed: 31306143
DOI: 10.3233/RNN-190926 -
The Annals of Pharmacotherapy May 2019To evaluate clinical trials using bumetanide in autism spectrum disorder (ASD) treatment. (Review)
Review
OBJECTIVE
To evaluate clinical trials using bumetanide in autism spectrum disorder (ASD) treatment.
DATA SOURCES
PubMed and Ovid MEDLINE (1946 to October 2018) were searched using terms bumetanide and autism. Bibliographies were reviewed for other relevant trials.
STUDY SELECTION AND DATA EXTRACTION
English language, randomized, controlled, clinical trials in humans were evaluated. Three trials met all inclusion criteria.
DATA SYNTHESIS
Oral bumetanide was studied in 208 patients, 2 to 18 years old, with ASD. Trials evaluated bumetanide's impact on core behavioral features using several different autism assessment scales. All trials used the Childhood Autism Rating Scale to assess improvement at 90 days, with one trial finding statistical significance. The Clinical Global Impressions Scale identified statistically significant improvements in 2 of the 3 trials. The Autism Behavioral Checklist and Social Responsiveness Scales identified statistical benefit in the 2 trials utilizing those outcomes. Behaviors most improved by bumetanide included social communication, interactions, and restricted interest. No dose-effect correlation was identified in the dose-ranging trial. Adverse effects, including hypokalemia and polyuria, occurred more often with higher doses and resulted in withdrawal rates of 17% to 43%. Bumetanide 0.5 mg twice daily was the most studied and best tolerated dose. Limitations included unclear clinical success definitions and evaluation methodology variability. Relevance to Patient Care and Clinical Practice: No effective treatment options for core ASD symptoms have been approved. This review presents preliminary safety and efficacy data for bumetanide in ASD.
CONCLUSIONS
Low-dose oral bumetanide may be useful in patients with moderate to severe ASD when behavioral therapies are not available.
Topics: Adolescent; Autism Spectrum Disorder; Bumetanide; Child; Child, Preschool; Female; Humans; Male; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 30501497
DOI: 10.1177/1060028018817304 -
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 -
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 -
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 -
Drug Intelligence & Clinical Pharmacy Nov 1983Bumetanide is a recently introduced diuretic that inhibits sodium transport in the thick ascending limb of the loop of Henle. It is structurally and pharmacologically... (Review)
Review
Bumetanide is a recently introduced diuretic that inhibits sodium transport in the thick ascending limb of the loop of Henle. It is structurally and pharmacologically similar to furosemide, but is approximately 40 times as potent on a milligram-for-milligram basis. After oral administration, it is rapidly absorbed, with peak serum concentrations attained at approximately 30 minutes. Its pharmacokinetic parameters are similar to those of furosemide. Bumetanide has demonstrated efficacy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and renal insufficiency. Bumetanide has demonstrated an adverse-reaction profile similar to that of furosemide, although the incidence of hypochloremia and hypokalemia is greater with bumetanide. The incidence of hyperglycemia and ototoxicity is greater with furosemide. The principal indication for bumetanide may be in patients with increased risk of ototoxicity. Cost considerations should relegate bumetanide to a secondary role for the treatment of sodium and fluid retention in most clinical settings.
Topics: Animals; Biopharmaceutics; Bumetanide; Carcinogens; Chemical Phenomena; Chemistry; Costs and Cost Analysis; Diuretics; Drug Interactions; Humans; Kidney Diseases; Kinetics; Liver Diseases; Mutagens; Protein Binding; Teratogens
PubMed: 6357686
DOI: 10.1177/106002808301701101 -
Epilepsia Jul 2022In his editorial, Kevin Staley criticizes our recent work demonstrating the lack of effect of bumetanide in a novel model of neonatal seizures. The main points in our...
In his editorial, Kevin Staley criticizes our recent work demonstrating the lack of effect of bumetanide in a novel model of neonatal seizures. The main points in our response are that (1) our work is on an asphyxia model, not one on "hypercarbia only"; (2) clinically relevant parenteral doses of bumetanide applied in vivo lead to concentrations in the brain parenchyma that are at least an order of magnitude lower than what would be sufficient to exert any direct effect-even a transient one-on neuronal functions, including neonatal seizures; and (3) moreover, bumetanide's molecular target in the brain is the Na-K-2Cl cotransporter NKCC1, which has vital functions in neurons, astrocytes, and oligodendrocytes as well as microglia. This would make it impossible even for highly brain-permeant NKCC1 blockers to specifically target depolarizing and excitatory actions of γ-aminobutyric acid in principal neurons of the brain, which is postulated as the rationale of clinical trials on neonatal seizures.
Topics: Bumetanide; Epilepsy; Humans; Infant, Newborn; Infant, Newborn, Diseases; Seizures; Sodium Potassium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 2
PubMed: 35524446
DOI: 10.1111/epi.17279 -
Drugs Nov 1984Bumetanide is a potent 'loop' diuretic for the treatment of oedema associated with congestive heart failure, hepatic and renal diseases, acute pulmonary congestion and... (Clinical Trial)
Clinical Trial Review
Bumetanide is a potent 'loop' diuretic for the treatment of oedema associated with congestive heart failure, hepatic and renal diseases, acute pulmonary congestion and premenstrual syndrome and in forced diuresis during and after surgery. Bumetanide may be given orally, intravenously or intramuscularly and produces a rapid and marked diuresis, and increased urinary excretion of sodium, chloride and other electrolytes (within 30 minutes) which persists for 3 to 6 hours. Its principal site of action is on the ascending limb of the loop of Henle, with a secondary action on the proximal tubule. Pharmacologically, bumetanide is about 40-fold more potent than frusemide (furosemide), with the exception of its effects on urinary potassium excretion where its potency is lower. Studies in patients with oedema due to congestive heart failure, pulmonary oedema or hepatic disease show that oral or intravenous bumetanide 0.5 to 2 mg/day produces results comparable to those with frusemide 20 to 80 mg/day. In acute pulmonary oedema, intravenous bumetanide produces a very rapid diuresis. Higher doses of bumetanide may be required (up to 15 mg/day) in patients with chronic renal failure or nephrotic syndrome. In these patients muscle cramps are not uncommon with bumetanide, but glomerular filtration rates are unaffected. In most studies, diuretic effects were accompanied by decreased bodyweight, abdominal girth and improvements in a variety of haemodynamic parameters. Comparison of bumetanide with frusemide at a dose ratio of 1 : 40 reveals no significant differences in clinical response with the exception of renal disease, where patients with oedema appear to respond better to bumetanide. Combination with thiazide diuretics enhances the clinical response to bumetanide. Potassium supplements and spironolactone may be beneficial additions to bumetanide where patients at risk of hypokalaemia can be identified. Clinically important side effects are infrequent, with audiological impairment occurring to a lesser extent than with frusemide. Bumetanide thus offers an important alternative to frusemide when a 'loop' diuretic is indicated.
Topics: Animals; Bumetanide; Carbonic Anhydrase Inhibitors; Clinical Trials as Topic; Diuretics; Heart Failure; Humans; Kallikreins; Kidney; Kidney Diseases; Kinetics; Liver Diseases; Parathyroid Hormone; Pulmonary Edema; Renin; Water-Electrolyte Balance
PubMed: 6391889
DOI: 10.2165/00003495-198428050-00003 -
Acta Pharmacologica Et Toxicologica 1977
Review
Topics: Animals; Bumetanide; Chemical Phenomena; Chemistry; Diuresis; Diuretics; Dogs; Electrolytes; Kidney; Mice; Osmolar Concentration; Rabbits; Rats; Regional Blood Flow; Renin
PubMed: 331869
DOI: 10.1111/j.1600-0773.1977.tb03209.x -
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