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Scientific Reports Oct 2020The measurement of electric potential and resistance reflect the transport of sodium and chloride ions which take place in keratinocytes and is associated with skin...
The measurement of electric potential and resistance reflect the transport of sodium and chloride ions which take place in keratinocytes and is associated with skin response to stimuli arising from external and internal environment. The aim of the study was to assess changes in electrical resistance and the transport of chloride and sodium ions, under iso-osmotic conditions and following the use of inhibitors affecting these ions' transport, namely amiloride (A) and bumetanide (B). The experiment was performed on 104 fragments of rabbit skin, divided into three groups: control (n = 35), A-inhibited sodium transport (n = 33) and B-inhibited chloride transport (n = 36). Measurement of electrical resistance (R) and electrical potential (PD) confirmed tissue viability during the experiment, no statistically significant differences in relation to control conditions were noted. The minimal and maximal PD measured during stimulation confirmed the repeatability of the recorded reactions to the mechanical and mechanical-chemical stimulus for all examined groups. Measurement of PD during stimulation showed differences in the transport of sodium and chloride ions in each of the analyzed groups relative to the control. The statistical analysis of the PD measured in stationary conditions and during mechanical and/or mechanical-chemical stimulation proved that changes in sodium and chloride ion transport constitute the physiological response of keratinocytes to changes in environmental conditions for all applied experimental conditions. Assessment of transdermal ion transport changes may be a useful tool for assessing the skin condition with tendency to pain hyperactivity and hypersensitivity to xenobiotics.
Topics: Amiloride; Animals; Bumetanide; Chlorides; Electrophysiology; Epithelial Sodium Channel Blockers; Ion Transport; Rabbits; Skin; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 33093644
DOI: 10.1038/s41598-020-75275-3 -
Acta Paediatrica (Oslo, Norway : 1992) Aug 2012The loop diuretics furosemide and bumetanide are commonly used in neonatal intensive care units (NICUs). Furosemide, because of its actions on the ubiquitous Na(+) -K(+)... (Review)
Review
UNLABELLED
The loop diuretics furosemide and bumetanide are commonly used in neonatal intensive care units (NICUs). Furosemide, because of its actions on the ubiquitous Na(+) -K(+) -2Cl(-) isoform cotransporter and its promotion of prostanoid production and release, also has non-diuretic effects on vascular smooth muscle, airways, the ductus arteriosus and theoretically the gastrointestinal tract. Loop diuretics also affect the central nervous system through modulation of the GABA-A chloride channel.
CONCLUSION
The loop diuretics have a variety of biological effects that are potentially harmful as well as beneficial. Care should be taken with the use of these agents because the range of their effects may be broader than the single action sought by the prescribing physician.
Topics: Biomarkers; Bronchopulmonary Dysplasia; Bumetanide; Central Nervous System; Diuretics; Ductus Arteriosus; Furosemide; Gastrointestinal Tract; Humans; Hyaline Membrane Disease; Infant, Newborn; Infant, Premature; Intensive Care, Neonatal; Lung; Muscle, Smooth, Vascular; gamma-Aminobutyric Acid
PubMed: 22536874
DOI: 10.1111/j.1651-2227.2012.02699.x -
Frontiers in Immunology 2022Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with few medication options. Bumetanide, an FDA-approved diuretic, has been proposed as a...
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with few medication options. Bumetanide, an FDA-approved diuretic, has been proposed as a viable candidate to treat core symptoms of ASD, however, neither the brain region related to its effect nor the cell-specific mechanism(s) is clear. The availability of nanoparticles provides a viable way to identify pharmacological mechanisms for use in ASD. Here, we found that treatment with bumetanide, in a systemic and medial prefrontal cortex (mPFC) region-specific way, attenuated social deficits in BTBR mice. Furthermore, using poly (ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(bumetanide)], we showed that the administration of NP(bumetanide) in a mPFC region-specific way also alleviated the social deficits of BTBR mice. Mechanistically, the behavioral effect of NP(bumetanide) was dependent on selective microglia-specific targeting in the mPFC. Pharmacological depletion of microglia significantly reduced the effect of nanoencapsulation and depletion of microglia alone did not improve the social deficits in BTBR mice. These findings suggest the potential therapeutic capabilities of nanotechnology for ASD, as well as the relevant link between bumetanide and immune cells.
Topics: Animals; Autism Spectrum Disorder; Brain; Bumetanide; Disease Models, Animal; Mice; Mice, Inbred Strains
PubMed: 35693812
DOI: 10.3389/fimmu.2022.870577 -
Cells Aug 2022The specific NKCC1 cotransporter antagonist, bumetanide, attenuates the severity of Autism Spectrum Disorders (ASD), and many neurodevelopmental or neurodegenerative...
The specific NKCC1 cotransporter antagonist, bumetanide, attenuates the severity of Autism Spectrum Disorders (ASD), and many neurodevelopmental or neurodegenerative disorders in animal models and clinical trials. However, the pervasive expression of NKCC1 in many cell types throughout the body is thought to challenge the therapeutic efficacy of bumetanide. However, many peripheral functions, including intestinal, metabolic, or vascular, etc., are perturbed in brain disorders contributing to the neurological sequels. Alterations of these functions also increase the incidence of the disorder suggesting complex bidirectional links with the clinical manifestations. We suggest that a more holistic view of ASD and other disorders is warranted to account for the multiple sites impacted by the original intra-uterine insult. From this perspective, large-spectrum active repositioned drugs that act centrally and peripherally might constitute a useful approach to treating these disorders.
Topics: Animals; Autism Spectrum Disorder; Bumetanide; Solute Carrier Family 12, Member 2
PubMed: 35954263
DOI: 10.3390/cells11152419 -
CNS Neuroscience & Therapeutics Feb 2015Seizures triggered by acute injuries to the developing brain respond poorly to first-line medications that target the inhibitory chloride-permeable GABAA receptor....
BACKGROUND
Seizures triggered by acute injuries to the developing brain respond poorly to first-line medications that target the inhibitory chloride-permeable GABAA receptor. Neuronal injury is associated with profound increases in cytoplasmic chloride ([Cl(-)]i) resulting in depolarizing GABA signaling, higher seizure propensity and limited efficacy of GABAergic anticonvulsants. The Na(+)-K(+)-2Cl(-) (NKCC1) cotransporter blocker bumetanide reduces [Cl(-)]i and causes more negative GABA equilibrium potential in injured neurons. We therefore tested both the acute and chronic efficacy of bumetanide on early posttraumatic ictal-like epileptiform discharges and epileptogenesis.
METHODS
Acute hippocampal slices were used as a model of severe traumatic brain injury and posttraumatic epileptogenesis. Hippocampal slices were then incubated for 3 weeks. After a 1-week latent period, slice cultures developed chronic spontaneous ictal-like discharges. The anticonvulsant and anti-epileptogenic efficacy of bumetanide, phenobarbital, and the combination of these drugs was studied.
RESULTS
Bumetanide reduced the frequency and power of early posttraumatic ictal-like discharges in vitro and enhanced the anticonvulsant efficacy of phenobarbital. Continuous 2-3 weeks administration of bumetanide as well as phenobarbital in combination with bumetanide failed to prevent posttraumatic ictal-like discharges and epileptogenesis.
CONCLUSIONS
Our data demonstrate a persistent contribution of NKCC1 cotransport in posttraumatic ictal-like activity, presumably as a consequence of chronic alterations in neuronal chloride homeostasis and GABA-mediated inhibition. New strategies for more effective reduction in posttraumatic and seizure-induced [Cl(-)]i accumulation could provide the basis for effective treatments for posttraumatic epileptogenesis and the resultant seizures.
Topics: Action Potentials; Analysis of Variance; Animals; Anticonvulsants; Bumetanide; Chlorides; Dose-Response Relationship, Drug; Hippocampus; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Organ Culture Techniques; Phenobarbital; Receptors, Immunologic; Recombinant Fusion Proteins; Sodium Potassium Chloride Symporter Inhibitors; Time Factors
PubMed: 25495911
DOI: 10.1111/cns.12369 -
Single-case experimental designs for bumetanide across neurodevelopmental disorders: BUDDI protocol.BMC Psychiatry Jul 2022Bumetanide is a selective NKCC1 chloride importer antagonist which is being repurposed as a mechanism-based treatment for neurodevelopmental disorders (NDDs). Due to...
BACKGROUND
Bumetanide is a selective NKCC1 chloride importer antagonist which is being repurposed as a mechanism-based treatment for neurodevelopmental disorders (NDDs). Due to their specific actions, these kinds of interventions will only be effective in particular subsets of patients. To anticipate stratified application, we recently completed three bumetanide trials each focusing on different stratification strategies with the additional objective of deriving the most optimal endpoints. Here we publish the protocol of the post-trial access combined cohort study to confirm previous effects and stratification strategies in the trial cohorts and in new participants.
METHOD/DESIGN
Participants of the three previous cohorts and a new cohort will be subjected to 6 months bumetanide treatment using multiple baseline Single Case Experimental Designs. The primary outcome is the change, relative to baseline, in a set of patient reported outcome measures focused on direct and indirect effects of sensory processing difficulties. Secondary outcome measures include the conventional questionnaires 'social responsiveness scale', 'repetitive behavior scale', 'sensory profile' and 'aberrant behavior scale'. Resting-state EEG measurements will be performed at several time-points including at Tmax after the first administration. Assessment of cognitive endpoints will be conducted using the novel Emma Tool box, an in-house designed battery of computerized tests to measure neurocognitive functions in children.
DISCUSSION
This study aims to replicate previously shown effects of bumetanide in NDD subpopulations, validate a recently proposed treatment prediction effect methodology and refine endpoint measurements.
TRIAL REGISTRATION
EudraCT: 2020-002196-35, registered 16 November 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002196-35/NL.
Topics: Bumetanide; Child; Cohort Studies; Humans; Neurodevelopmental Disorders; Research Design; Treatment Outcome
PubMed: 35799144
DOI: 10.1186/s12888-022-04033-8 -
Kidney International Aug 1984We assessed the handling of and response to oral bumetanide (1.0 and 2.0 mg) and to furosemide (40 and 80 mg) in 20 patients with stable, compensated congestive heart... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
We assessed the handling of and response to oral bumetanide (1.0 and 2.0 mg) and to furosemide (40 and 80 mg) in 20 patients with stable, compensated congestive heart failure (CHF), comparing the two drugs and, in addition, examining differences from normal subjects. Bumetanide and furosemide were similar in time course of absorption, but patients with CHF had considerably prolonged absorption compared to normal subjects causing attainment of lower peak concentrations of drug. In both CHF and normal subjects, more bumetanide than furosemide was absorbed. The elimination half-life of furosemide was approximately twice that of bumetanide, and both were about two times longer than respective values in normal subjects. "Dose"-response curves were shifted downward from normal with both drugs. In patients with CHF, overall response did not differ between bumetanide and furosemide. The two drugs exhibit subtle differences, the clinical importance of which appears to be negligible from this study. Importantly, however, both drugs showed delayed absorption causing attainment of peak urinary excretion rates of diuretic two- to threefold lower than in normal subjects. This effect along with the abnormal responsivity of the tubule may contribute to the "resistance" to oral doses of diuretics observed clinically even though no quantitative malabsorption of drug occurs.
Topics: Absorption; Adult; Aged; Bumetanide; Diuretics; Dose-Response Relationship, Drug; Female; Furosemide; Glomerular Filtration Rate; Half-Life; Heart Failure; Humans; Kinetics; Male; Middle Aged; Tissue Distribution
PubMed: 6503136
DOI: 10.1038/ki.1984.153 -
Physiological Reviews Apr 2005Electroneutral cation-Cl(-) cotransporters compose a family of solute carriers in which cation (Na(+) or K(+)) movement through the plasma membrane is always accompanied... (Review)
Review
Electroneutral cation-Cl(-) cotransporters compose a family of solute carriers in which cation (Na(+) or K(+)) movement through the plasma membrane is always accompanied by Cl(-) in a 1:1 stoichiometry. Seven well-characterized members include one gene encoding the thiazide-sensitive Na(+)-Cl(-) cotransporter, two genes encoding loop diuretic-sensitive Na(+)-K(+)-2Cl(-) cotransporters, and four genes encoding K(+)-Cl(-) cotransporters. These membrane proteins are involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl(-) concentration below or above its electrochemical potential equilibrium. In addition, members of this family play an important role in cardiovascular and neuronal pharmacology and pathophysiology. Some of these cotransporters serve as targets for loop diuretics and thiazide-type diuretics, which are among the most commonly prescribed drugs in the world, and inactivating mutations of three members of the family cause inherited diseases such as Bartter's, Gitelman's, and Anderman's diseases. Major advances have been made in the past decade as consequences of molecular identification of all members in this family. This work is a comprehensive review of the knowledge that has evolved in this area and includes molecular biology of each gene, functional properties of identified cotransporters, structure-function relationships, and physiological and pathophysiological roles of each cotransporter.
Topics: Animals; Bumetanide; Cations; Chlorides; Electrochemistry; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Mutation; Receptors, Drug; Sodium Chloride Symporters; Sodium-Potassium-Chloride Symporters; Solute Carrier Family 12, Member 3; Symporters
PubMed: 15788703
DOI: 10.1152/physrev.00011.2004 -
Molecular Autism May 2020Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad... (Clinical Trial)
Clinical Trial
BACKGROUND
Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of γ-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC.
METHODS
Participants were treated with bumetanide (2dd 0.5-1.0 mg) for 13 weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91 days of treatment and after a 28-day wash-out period.
RESULTS
Fifteen patients (8-21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p = .001, d = .773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p = .002, d = .549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p = .003, d = .686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency.
LIMITATIONS
The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures.
CONCLUSIONS
Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.
Topics: Adolescent; Autism Spectrum Disorder; Bumetanide; Child; Disease Susceptibility; Duration of Therapy; Electroencephalography; Evoked Potentials; Female; Humans; Male; Neurodevelopmental Disorders; Neuropsychological Tests; Pilot Projects; Quality of Life; Sodium Potassium Chloride Symporter Inhibitors; Surveys and Questionnaires; Treatment Outcome; Tuberous Sclerosis; Young Adult
PubMed: 32381101
DOI: 10.1186/s13229-020-00335-4 -
The Journal of Physiology Nov 2020
Topics: Biological Transport; Bodily Secretions; Bumetanide; Choroid Plexus; Phenobarbital
PubMed: 32870502
DOI: 10.1113/JP280493