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Epilepsia Feb 2016We investigated the role of chloride homeostasis in seizure progression and development of pharmacoresistant status epilepticus (SE) by pharmacologically targeting the...
OBJECTIVE
We investigated the role of chloride homeostasis in seizure progression and development of pharmacoresistant status epilepticus (SE) by pharmacologically targeting the Na-K-Cl cotransporter (NKCC1) with bumetanide. We also investigated the ability of bumetanide to restore the efficacy of diazepam following SE.
METHODS
Kainic acid (KA)-induced SE in vivo and 0-Mg(2+) -induced seizure-like events (SLEs) in vitro were monitored using electroencephalography (EEG) recordings in freely moving adult male mice and extracellular field potential recordings in acute entorhinal cortex-hippocampus slices, respectively. The ability of bumetanide to decrease epileptiform activity and prevent the development of pharmacoresistance to diazepam following SE was evaluated.
RESULTS
Bumetanide treatment significantly reduced KA-induced ictal activity in vivo and SLEs in vitro. In addition, bumetanide restored the efficacy of diazepam in decreasing ictal activity following SE in both the in vivo and in vitro models.
SIGNIFICANCE
Our data demonstrate an anticonvulsant effect of bumetanide on KA-induced seizures in adult mice, suggesting a role for chloride plasticity in seizure progression. These data also demonstrate that the erosion of inhibition during seizure progression could underlie the development of pharmacoresistant SE and implicate a role for chloride plasticity in this process.
Topics: Animals; Anticonvulsants; Brain; Bumetanide; Diazepam; Disease Progression; Drug Resistant Epilepsy; Electroencephalography; Entorhinal Cortex; Excitatory Amino Acid Agonists; Hippocampus; In Vitro Techniques; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Seizures; Sodium Potassium Chloride Symporter Inhibitors; Status Epilepticus
PubMed: 26659482
DOI: 10.1111/epi.13270 -
Neuropharmacology Jan 2020Temporal lobe epilepsy (TLE) is the most common type of focal epilepsies, affecting approximately 35 million people worldwide. Despite the introduction of numerous novel...
Temporal lobe epilepsy (TLE) is the most common type of focal epilepsies, affecting approximately 35 million people worldwide. Despite the introduction of numerous novel antiepileptic drugs during the last decades, the proportion of patients with therapy-resistant TLE is still high. As an impaired cellular chloride homeostasis appears involved in disease pathophysiology, bumetanide, an antagonist to Na-K-Cl cotransporters, gained interest as potential therapeutic option. However, bumetanide induces a strong diuretic effect and displays poor penetration across the blood-brain barrier (BBB). To reduce these unwanted effects, we modified the already described BUM690 by exchanging the allyl-into a trifluoro-ethyl group to yield BUM532. Furthermore, we exchanged the nitrogen for oxygen in the trifluoro-ethyl group to yield BUM97. In the intrahippocampal kainic acid mouse model of TLE BUM532 ± phenobarbital (PB), bumetanide ± PB and PB alone significantly reduced hippocampal paroxysmal discharges (HPDs) but not spike trains. By contrast, treatment with BUM97 suppressed HPDs as well as spike trains dose-dependently, more pronounced compared to the other tested compounds and exerted a synergistic anticonvulsant effect with PB. Moreover, at higher doses BUM97 achieved long-lasting reduction of spike trains. In pentylenetetrazole-induced acute seizures only BUM532 combined with a sub-effective dose of PB increased the seizure threshold. No diuretic effects were observed at any dose of the three derivatives. Our data demonstrate the successful optimization of the pharmacological profile of bumetanide and the potential of the improved derivative BUM97 for the treatment of therapy-resistant TLE, in particular in combinatorial drug regimens with a GABA mimetic.
Topics: Animals; Anticonvulsants; Blood-Brain Barrier; Brain; Bumetanide; Convulsants; Disease Models, Animal; Diuretics; Dose-Response Relationship, Drug; Drug Resistant Epilepsy; Electroencephalography; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; Kainic Acid; Mice; Pentylenetetrazole; Phenobarbital; Seizures; Sodium Potassium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 2
PubMed: 31476353
DOI: 10.1016/j.neuropharm.2019.107754 -
Biological & Pharmaceutical Bulletin 2016Epileptogenesis, which can be initiated by brain insults or gene mutations in the normal brain, is defined as the gradual (months to years) process of epilepsy... (Review)
Review
Epileptogenesis, which can be initiated by brain insults or gene mutations in the normal brain, is defined as the gradual (months to years) process of epilepsy development that begins before the first epileptic seizure. Epileptogenic changes include induction of immediate early genes, post-translational modification of ion-channel functions, neuronal death, gliosis, and reorganization of neural circuits. Each of these changes alone or in combination can contribute to an epileptogenic focus, which is defined by the minimal cortical region that is necessary and sufficient to induce synchronized epileptic bursting activity in neurons. Therefore to discover and develop anti-epileptogenic drugs it is essential to unveil the cellular and molecular mechanisms underlying the development of epileptogenic foci. Among the epileptogenic changes, abnormally appended excitatory recurrent circuits can directly cause synchronized bursting of neuron activity. Here, I will introduce and discuss the mechanisms underlying the development of two representative abnormal neural circuits, namely, hippocampal mossy fiber sprouting and ectopic granule cells, which are found in the dentate gyrus of patients with mesial temporal lobe epilepsy and its animal models.
Topics: Animals; Anticonvulsants; Bumetanide; Dentate Gyrus; Epilepsy; Humans
PubMed: 27251488
DOI: 10.1248/bpb.b16-00125 -
Clinical Pharmacology and Therapeutics Nov 1988Four healthy subjects and six patients with congestive heart failure (CHF) were given 3 mg oral and intravenous doses of bumetanide in a random crossover fashion.... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Four healthy subjects and six patients with congestive heart failure (CHF) were given 3 mg oral and intravenous doses of bumetanide in a random crossover fashion. Bumetanide was analyzed by HPLC, and sodium and potassium was analyzed by flame photometry. Aside from a modest reduction in renal clearance, the kinetics of bumetanide in CHF were similar to those in healthy subjects. The extent of bioavailability was 81%, with a variability of 20% to 25% about the mean for both groups. The cumulative dynamic responses to bumetanide, whether administered orally or intravenously, were essentially the same in each group. Pharmacodynamic modeling showed that there were no significant differences between healthy subjects and patients with CHF in either ER50 (bumetanide urinary excretion rate producing 50% of maximum drug effect) or S (slope), although the baseline effect was 15 times lower in CHF. The maximum effect attributable to bumetanide was twofold higher in healthy subjects and there was a significant correlation between this parameter and creatinine clearance (r = 0.964; p less than 0.001). Overall, these results indicate that a predictable transition from 3 mg intravenous to oral doses of bumetanide is possible in CHF.
Topics: Administration, Oral; Adult; Aged; Biological Availability; Blood Proteins; Bumetanide; Diuretics; Dose-Response Relationship, Drug; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Middle Aged; Random Allocation
PubMed: 3180632
DOI: 10.1038/clpt.1988.186 -
Scientific Reports Jun 2018The Na-K-2Cl cotransporter NKCC1 plays a role in neuronal Cl homeostasis secretion and represents a target for brain pathologies with altered NKCC1 function. Two main... (Comparative Study)
Comparative Study
The Na-K-2Cl cotransporter NKCC1 plays a role in neuronal Cl homeostasis secretion and represents a target for brain pathologies with altered NKCC1 function. Two main variants of NKCC1 have been identified: a full-length NKCC1 transcript (NKCC1A) and a shorter splice variant (NKCC1B) that is particularly enriched in the brain. The loop diuretic bumetanide is often used to inhibit NKCC1 in brain disorders, but only poorly crosses the blood-brain barrier. We determined the sensitivity of the two human NKCC1 splice variants to bumetanide and various other chemically diverse loop diuretics, using the Xenopus oocyte heterologous expression system. Azosemide was the most potent NKCC1 inhibitor (ICs 0.246 µM for hNKCC1A and 0.197 µM for NKCC1B), being about 4-times more potent than bumetanide. Structurally, a carboxylic group as in bumetanide was not a prerequisite for potent NKCC1 inhibition, whereas loop diuretics without a sulfonamide group were less potent. None of the drugs tested were selective for hNKCC1B vs. hNKCC1A, indicating that loop diuretics are not a useful starting point to design NKCC1B-specific compounds. Azosemide was found to exert an unexpectedly potent inhibitory effect and as a non-acidic compound, it is more likely to cross the blood-brain barrier than bumetanide.
Topics: Animals; Biological Transport; Brain; Bumetanide; Chlorides; Diuretics; Homeostasis; Humans; Sodium Potassium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 2; Sulfanilamides
PubMed: 29959396
DOI: 10.1038/s41598-018-27995-w -
Biological Psychiatry. Cognitive... Mar 2023Mechanism-based treatments such as bumetanide are being repurposed for autism spectrum disorder. We recently reported beneficial effects on repetitive behavioral... (Randomized Controlled Trial)
Randomized Controlled Trial
Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder.
BACKGROUND
Mechanism-based treatments such as bumetanide are being repurposed for autism spectrum disorder. We recently reported beneficial effects on repetitive behavioral symptoms that might be related to regulating excitation-inhibition (E/I) balance in the brain. Here, we tested the neurophysiological effects of bumetanide and the relationship to clinical outcome variability and investigated the potential for machine learning-based predictions of meaningful clinical improvement.
METHODS
Using modified linear mixed models applied to intention-to-treat population, we analyzed E/I-sensitive electroencephalography (EEG) measures before and after 91 days of treatment in the double-blind, randomized, placebo-controlled Bumetanide in Autism Medication and Biomarker study. Resting-state EEG of 82 subjects out of 92 participants (7-15 years) were available. Alpha frequency band absolute and relative power, central frequency, long-range temporal correlations, and functional E/I ratio treatment effects were related to the Repetitive Behavior Scale-Revised (RBS-R) and the Social Responsiveness Scale 2 as clinical outcomes.
RESULTS
We observed superior bumetanide effects on EEG, reflected in increased absolute and relative alpha power and functional E/I ratio and in decreased central frequency. Associations between EEG and clinical outcome change were restricted to subgroups with medium to high RBS-R improvement. Using machine learning, medium and high RBS-R improvement could be predicted by baseline RBS-R score and EEG measures with 80% and 92% accuracy, respectively.
CONCLUSIONS
Bumetanide exerts neurophysiological effects related to clinical changes in more responsive subsets, in whom prediction of improvement was feasible through EEG and clinical measures.
Topics: Humans; Autism Spectrum Disorder; Bumetanide; Electroencephalography; Treatment Outcome
PubMed: 34506972
DOI: 10.1016/j.bpsc.2021.08.009 -
British Journal of Clinical Pharmacology Feb 19831 Bumetanide (1 mg) was given orally and intravenously to a group of patients with chronic renal failure (n = 6) and to another group with cirrhosis of the liver (n =...
1 Bumetanide (1 mg) was given orally and intravenously to a group of patients with chronic renal failure (n = 6) and to another group with cirrhosis of the liver (n = 8). 2 The pharmacokinetics, using a two-compartment model, and the pharmacodynamics of the drug in these patients were compared with those previously obtained for normal subjects. 3 In the renal group serum bumetanide concentrations were higher than for the normal subjects and the terminal half-lives were significantly prolonged (P less than 0.001). A decreased whole body clearance was attributable to a low renal clearance of drug, the non-renal clearance being significantly increased (P less than 0.01). 4 For the patients with liver disease, serum bumetanide concentrations were higher than for the renal group, and the terminal half-lives were significantly further prolonged (P less than 0.001). Both non-renal and renal clearances were significantly reduced (P less than 0.001). 5 Absorption rates were not significantly altered in either group and the values of F (bioavailability) were 0.82 and 0.95 for the patients with renal disease and hepatic disease, respectively. 6 A poor pharmacodynamic response and a reduced bumetanide excretion rate were observed for the patients with chronic renal failure, whereas with hepatic disease normal bumetanide excretion rates were observed with an impaired diuretic response.
Topics: Administration, Oral; Adult; Aged; Bumetanide; Diuretics; Humans; Injections, Intravenous; Kidney Failure, Chronic; Kinetics; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Middle Aged
PubMed: 6849758
DOI: 10.1111/j.1365-2125.1983.tb01493.x -
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 -
The Journal of Biological Chemistry Sep 1997The Na-K-Cl cotransporter (NKCC) plays a key role in electrolyte secretion and absorption across polarized epithelia. The structure of the Na-K-Cl cotransporter...
The Na-K-Cl cotransporter (NKCC) plays a key role in electrolyte secretion and absorption across polarized epithelia. The structure of the Na-K-Cl cotransporter transport protein is not known, but from analysis of the primary amino acid sequence and biochemical studies, it has been inferred that the protein has large cytoplasmic N and C termini and a hydrophobic central domain containing 12 transmembrane helices. Both the central domain and the C-terminal domain are highly conserved within the cation-chloride cotransporter family. This paper examines the role of these three domains in interacting with the transported ions and with the inhibitor bumetanide. We have used a chimera approach, exploiting the functional differences between the structurally similar shark and human secretory Na-K-Cl cotransporters (sNKCC1 and hNKCC1). These transporters are 74% identical to one another and have similar transport and regulatory behaviors; however, sNKCC1 differs markedly from hNKCC1 with regard to apparent affinities for the cotransported ions and for bumetanide. We prepared six sNKCC1-hNKCC1 chimeras in which N and C termini were interchanged between species. When transfected in HEK-293 cells, each chimera carried out bumetanide-sensitive 86Rb influx, demonstrating transporter synthesis and cell surface delivery. Monoclonal antibodies J3 and J7 were used to detect the chimeric proteins, and the epitopes for these antibodies were localized to residues 49-196 and 1050-1168, respectively, in the shark sequence. For each of two chimeras that were examined, the time course of activation in low Cl- medium was the same as for the parent proteins; activation was found to proceed through a change in Vmax rather than Km. For the six chimeras, the apparent affinities for Na+, K+, Cl-, and bumetanide segregated exactly according to whether the large hydrophobic central domain was derived from sNKCC1 or hNKCC1. Significantly, the well-conserved C terminus does not appear to contain residues involved in the shark-human affinity differences. These results demonstrate that residues involved with ion translocation and inhibitor binding are within the large central domain that contains the 12 predicted transmembrane helices.
Topics: Animals; Bumetanide; Carrier Proteins; Cell Membrane; Chlorides; Epitope Mapping; Humans; Ions; Kinetics; Microscopy, Fluorescence; Potassium; Recombinant Fusion Proteins; Sequence Deletion; Sodium; Sodium-Potassium-Chloride Symporters
PubMed: 9305921
DOI: 10.1074/jbc.272.39.24556 -
Science Bulletin Aug 2021With the current limited drug therapy for the core symptoms of autism spectrum disorder (ASD), we herein report a randomized, double-blind, placebo-controlled trial to... (Randomized Controlled Trial)
Randomized Controlled Trial
With the current limited drug therapy for the core symptoms of autism spectrum disorder (ASD), we herein report a randomized, double-blind, placebo-controlled trial to investigate the efficacy, safety, and potential neural mechanism of bumetanide in children with ASD aged 3-6 years old. A total of 120 children were enrolled into the study and randomly assigned to either 0.5 mg bumetanide or placebo. In the final sample, 119 children received at least one dose of bumetanide (59 children) or placebo (60 children) were included in the final analysis. The primary outcome was a reduction in the Childhood Autism Rating Scale (CARS) score, and the secondary outcomes were the Clinical Global Impressions Scale (CGI) -Global Improvement (CGI-I) score at 3 months and the change from baseline to 3-month in the Autism Diagnostic Observation Schedule (ADOS). Magnetic resonance spectroscopy (MRS) was used to measure γ-aminobutyric acid (GABA) and glutamate neurotransmitter concentrations in the insular cortex (IC) before and after the treatment. As compared with the placebo, bumetanide treatment was significantly better in reducing the severity. No patient withdrew from the trial due to adverse events. The superiority of bumetanide to placebo in reducing insular GABA, measured using MRS, was demonstrated. The clinical improvement was associated with a decrease in insular GABA in the bumetanide group. In conclusion, this trial in a large group of young children with predominantly moderate and severe ASD demonstrated that bumetanide is safe and effective in improving the core symptoms of ASD. However, the clinical significance remains uncertain, and future multi-center clinical trials are required to replicate these findings and confirm the clinical significance using a variety of outcome measures.
Topics: Humans; Child; Child, Preschool; Bumetanide; Autism Spectrum Disorder; Autistic Disorder; Glutamic Acid; gamma-Aminobutyric Acid
PubMed: 36654288
DOI: 10.1016/j.scib.2021.01.008