Effects of bumetanide: A Synthesis of Findings from 24 Studies

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Original Abstract of the Article

Major Research Findings

Bumetanide is a loop diuretic that has been studied for its potential therapeutic effects on various neurological disorders, including autism spectrum disorder (ASD), epilepsy, and stroke. Bumetanide acts by inhibiting the sodium-potassium-chloride cotransporter (NKCC1), which plays a crucial role in regulating chloride concentration within cells.

One key finding is that bumetanide can improve core symptoms of ASD in children, as demonstrated by a multicenter phase 2B study 8 . This study showed that bumetanide significantly improved scores on the Childhood Autism Rating Scale (CARS), the Social Responsiveness Scale (SRS), and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Further supporting this potential, a separate study 16 reported that bumetanide reduced autistic behavior in infants. These findings suggest that bumetanide could be a valuable therapeutic agent for ASD.

However, another study 2 found that bumetanide did not improve neurocognitive function in children with ASD. This suggests that bumetanide may not be effective for all ASD symptoms. Furthermore, research on the effects of bumetanide in epilepsy has yielded mixed results. While 19 showed that bumetanide could alleviate seizures in newborn rats, another study 4 found that it was not effective in preventing seizures in adult epileptic mice. These findings highlight the need for further research to better understand the specific applications and potential limitations of bumetanide in various neurological disorders.

Benefits and Risks

Benefit Summary

Bumetanide has shown potential benefits in treating a variety of neurological disorders, including autism spectrum disorder (ASD), epilepsy, and stroke. 8 and 16 suggest that bumetanide can improve core symptoms of ASD in children. Bumetanide might also play a role in improving the effects of other anti-seizure medications, as demonstrated in studies using a rat model of birth asphyxia 1 .

Risk Summary

Bumetanide can cause side effects, including hypokalemia (low potassium levels). The frequency and incidence of adverse events are directly correlated with the dose of bumetanide 8 . Additionally, bumetanide has limited penetration into the brain, potentially requiring higher doses to be effective. These factors highlight the importance of careful monitoring and dose adjustment under the guidance of a healthcare professional.

Comparison Across Studies

Commonalities Across Studies

Numerous studies have investigated the potential therapeutic effects of bumetanide on various neurological disorders. A common thread across these studies is the proposed mechanism of action: bumetanide inhibits NKCC1, which regulates chloride concentration within cells, thereby impacting the function of neurotransmitters like GABA. This suggests that bumetanide may act by modulating neuronal excitability, potentially reducing symptoms associated with neurological disorders.

Differences Across Studies

Despite the proposed common mechanism, the effectiveness of bumetanide has varied across different studies and neurological conditions. 8 and 16 suggest that bumetanide is beneficial for ASD, but 2 shows no impact on neurocognitive function. Similarly, bumetanide has shown efficacy in neonatal seizure models 19 but not in adult epileptic mice 4 . This disparity in results emphasizes the need for further investigation to understand the specific conditions and patient populations where bumetanide may be most effective.

Consistency and Contradictions of Results

The results regarding the efficacy of bumetanide in neurological disorders have not been entirely consistent. Some studies have shown promising results, while others have not. This inconsistency may be due to factors such as age, specific neurological condition, dosage, and individual patient variations. Further research is needed to clarify the specific circumstances under which bumetanide is most effective.

Implications for Real-World Application

The potential benefits of bumetanide in treating neurological disorders warrant further exploration. However, it's crucial to remember that bumetanide is a prescription medication that should only be used under the supervision of a healthcare professional. It is essential to discuss the potential benefits and risks with a doctor to determine if bumetanide is appropriate for you.

Current Research Limitations

The research on bumetanide's effectiveness in treating neurological disorders is still ongoing. There are gaps in our understanding of its precise mechanism of action, its optimal dosage, and the full range of its benefits and risks. Further research is essential to address these limitations and provide more comprehensive guidance for clinical use.

Future Directions for Research

To advance our understanding of bumetanide and its potential therapeutic value, future research should focus on the following areas: * Elucidating the detailed mechanism of action of bumetanide in various neurological disorders. * Conducting more comprehensive studies to assess the efficacy and safety of bumetanide in different patient populations and disease subtypes. * Developing strategies to optimize the delivery and effectiveness of bumetanide, such as improving its brain penetration. * Exploring the potential for bumetanide in combination therapies with other treatments for neurological disorders.

Conclusion

Bumetanide has emerged as a promising therapeutic agent for certain neurological disorders. However, more research is required to establish its specific roles and limitations. Always consult a healthcare professional to discuss the potential benefits and risks of bumetanide before considering its use. Continued research will be essential to further our understanding of this medication and its potential to improve the lives of those affected by neurological disorders.

Literature analysis of 24 papers
Positive Content
19
Neutral Content
2
Negative Content
3
Article Type
1
0
0
2
24
1.

Bumetanide potentiates the anti-seizure and disease-modifying effects of midazolam in a noninvasive rat model of term birth asphyxia.

Author: WelzelBjörn, JohneMarie, LöscherWolfgang

Cognitive function improvement
Neonatal seizure treatment
Neuron loss prevention

Bumetanide, a loop diuretic, can enhance the effectiveness of midazolam in preventing seizures in a rat model of birth asphyxia. This combination also improves long-term cognitive function.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

3.

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study.

Author: Juarez-MartinezErika L, van AndelDorinde M, SprengersJan J, AvramieaArthur-Ervin, OranjeBob, ScheepersFloortje E, JansenFloor E, MansvelderHuibert D, Linkenkaer-HansenKlaus, BruiningHilgo

Chloride homeostasis correction
Improved behavioral symptoms

This study investigated the effects of bumetanide, a chloride-regulating agent, on brain activity in children with tuberous sclerosis complex (TSC). The study found that bumetanide increased alpha-band absolute power in the brain, which may suggest improvement in neuronal excitation-inhibition balance.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

4.

Effects of the NKCC1 inhibitors bumetanide, azosemide, and torasemide alone or in combination with phenobarbital on seizure threshold in epileptic and nonepileptic mice.

Author: HampelPhilip, RömermannKerstin, GailusBjörn, JohneMarie, GerickeBirthe, KaczmarekEdith, LöscherWolfgang

Increased seizure threshold
Variable efficacy upon repeated MEST determinations

The loop diuretics azosemide, bumetanide, and torasemide, which all block NKCC1, were not effective in increasing seizure threshold in adult epilepsy.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

5.

Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study.

Author: van AndelDorinde M, SprengersJan J, OranjeBob, ScheepersFloortje E, JansenFloor E, BruiningHilgo

TSC treatment

Bumetanide, a selective NKCC1 chloride importer antagonist, showed potential in a pilot study to improve neurophysiological, cognitive, and behavioral measures in children with tuberous sclerosis complex (TSC).

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

6.

Bumetanide: A review of its neuroplasticity and behavioral effects after stroke.

Author: TaoDongxia, LiuFangxi, SunXiaoyu, QuHuiling, ZhaoShanshan, ZhouZhike, XiaoTing, ZhaoChuansheng, ZhaoMei

Neuroplasticity enhancement
Stroke recovery

This review discusses the potential of bumetanide, a Na+-K+-Cl- co-transporter inhibitor, as a treatment for stroke recovery. Bumetanide may improve functional recovery after stroke by reducing brain damage and promoting neuroplasticity.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

7.

Longitudinal Effects of Bumetanide on Neuro-Cognitive Functioning in Drug-Resistant Epilepsy.

Author: GharaylouZeinab, ShafaghiLida, OghabianMohammad Ali, YoonessiAli, TafakhoriAbbas, Shahsavand AnanlooEsmaeil, HadjighassemMahmoudreza

Cognitive improvement
Epilepsy treatment

This study evaluated the longitudinal effects of bumetanide, an NKCC1 co-transporter antagonist, on brain microstructure and cognitive performance in patients with refractory epilepsy. Bumetanide reduced seizure frequency and improved cognitive functions, potentially through white matter reconstruction.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

8.

Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders.

Author: LemonnierE, VilleneuveN, SonieS, SerretS, RosierA, RoueM, BrossetP, ViellardM, BernouxD, RondeauS, ThummlerS, RavelD, Ben-AriY

ASD treatment
Diarrhea
Hypokalemia
Loss of appetite

Bumetanide, an NKCC1 chloride-importer inhibitor, is a potential treatment for autism spectrum disorder (ASD). This study evaluated the dose/response and safety effects of bumetanide in 88 patients with ASD. The study found that bumetanide significantly improved the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily.

Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

9.

Anti-angiogenic Effects of Bumetanide Revealed by DCE-MRI with a Biodegradable Macromolecular Contrast Agent in a Colon Cancer Model.

Author: MalamasAnthony S, JinErlei, ZhangQi, HaagaJohn, LuZheng-Rong

Reduced plasma volume
Reduced vascular permeability
Uninterrupted tumor expansion

Bumetanide treatment reduced vascular permeability and plasma volume fraction in nude mice bearing flank HT29 colon cancer xenografts, as measured by dynamic contrast enhanced (DCE)-MRI with a biodegradable macromolecular MRI contrast agent. Bumetanide has potential to curtail growth of the tumor vasculature.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.

Language : English

10.

In vivo effects of bumetanide at brain concentrations incompatible with NKCC1 inhibition on newborn DGC structure and spontaneous EEG seizures following hypoxia-induced neonatal seizures.

Author: WangS, ZhangX Q, SongC G, XiaoT, ZhaoM, ZhuG, ZhaoC S

Dendritic development
Enhanced cell proliferation
Suppression of seizure activity
Incompatibility with NKCC1 inhibition
Lower brain concentrations

Bumetanide, a NKCC1 inhibitor, showed long-term effects on suppressing seizure activity and altering neurogenesis after neonatal seizures in a rat model.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

11.

A novel prodrug-based strategy to increase effects of bumetanide in epilepsy.

Author: TöllnerKathrin, BrandtClaudia, TöpferManuel, BrunhoferGerda, ErkerThomas, GabrielMario, FeitPeter W, LindforsJenna, KailaKai, LöscherWolfgang

Neurological disease treatment
Diuretic effect
Poor brain penetration

Bumetanide, a Na-K-Cl cotransporter antagonist, has potential for treating neurological diseases, but its heavy protein binding and potent diuretic effects limit its use.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

12.

Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy.

Author: TöpferManuel, TöllnerKathrin, BrandtClaudia, TweleFriederike, BröerSonja, LöscherWolfgang

Epilepsy treatment

Bumetanide, a diuretic that blocks the Na-K-Cl cotransporter (NKCC), is used to inhibit neuronal NKCC1, particularly in brain diseases like epilepsy. However, bumetanide has poor brain penetration and is rapidly eliminated in rodents due to N-butyl sidechain oxidation. Piperonyl butoxide (PBO) inhibits oxidation, increasing bumetanide's half-life and diuretic activity in rats. This study investigated whether PBO increases bumetanide brain levels in rats and mice and alters pharmacodynamic effects in the kindling model of epilepsy. PBO increased bumetanide's half-life in mice to human levels, significantly elevating brain levels. In rats, the increase was less pronounced. PBO increased bumetanide's diuretic activity, but did not suppress spontaneous seizures in epileptic mice. Bumetanide, with or without PBO, did not affect fully kindled seizures but altered kindling development in rats. PBO enhances the translational value of rodent experiments with bumetanide, particularly in mice.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

13.

Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis.

Author: WuFenfen, MiWentao, CannonStephen C

Improved hypokalaemic periodic paralysis
Side effects

Bumetanide, a chloride influx inhibitor, showed protection against muscle weakness in mouse models of hypokalaemic periodic paralysis, suggesting potential therapeutic value for this condition.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

14.

The extracellular space and epileptic activity in the adult brain: explaining the antiepileptic effects of furosemide and bumetanide.

Author: HochmanDaryl W

Block epileptiform activity

This study explored the role of the extracellular space (ECS), the fluid surrounding brain cells, in epilepsy. Treatments that reduce the size of the ECS, such as loop diuretics (furosemide and bumetanide), were found to block epileptiform activity, the abnormal electrical activity in the brain that causes seizures. The study suggests that activity-driven changes in the size of the ECS are important for maintaining epileptiform activity and that reducing ECS size could be a potential treatment for epilepsy.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

15.

Age- and region-specific effects of anticonvulsants and bumetanide on 4-aminopyridine-induced seizure-like events in immature rat hippocampal-entorhinal cortex slices.

Author: WahabAbdul, AlbusKlaus, HeinemannUwe

Reduced seizures

This study found that seizure-like events (SLEs) induced by 4-aminopyridine in immature rat organotypic slice cultures were resistant to standard antiepileptic drugs. The study also found that bumetanide, a blocker of the Na(+)-K(+)-2Cl(-) (NKCC1) cotransporter, blocked SLEs in the CA3 region of the hippocampus, suggesting that expression of the NKCC1 cotransporter might contribute to pharmacoresistance.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

16.

The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects.

Author: LemonnierEric, Ben-AriYehezkel

Reduced autistic behavior

Bumetanide decreases autistic behaviour with no side effects suggesting that diuretic agents may exert beneficial effects on IAS and that alterations of the actions of GABA may be efficient in IAS treatment calling for large scale randomized trials.

Evaluation StudyResearch that systematically evaluates the effectiveness of a particular program or policy. It measures its outcomes and provides important information for future decision-making.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

18.

Bumetanide-induced enlargement of the rat intrastrial space and effects of a vasopressin type 2 antagonist.

Author: NishimuraMasahiko, KakigiAkinobu, TakedaTaizo, OkadaTeruhiko, DoiKatsumi

Enlarged intrastrial space

This study investigates the influence of OPC-31260, a vasopressin type 2 antagonist, on the experimentally induced enlargement of the intrastrial space caused by bumetanide, an inhibitor of Na(+)-K(+)-2Cl(-) co-transporter (NKCC).

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

19.

Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain.

Author: EdwardsDavid A, ShahHina P, CaoWengang, GravensteinNikolaus, SeubertChristoph N, MartynyukAnatoly E

Decreases caspase-3
Decreases seizures
Respiratory depression
Seizures

Sevoflurane anesthesia in newborn rats was associated with seizures, neurotoxicity, and impairment of synaptic plasticity. Bumetanide, a Na-K-2Cl cotransporter 1 inhibitor, significantly decreased seizures in younger rats but did not affect the neurotoxic effects.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

20.

Cerebral metabolic alterations in rats with diabetic ketoacidosis: effects of treatment with insulin and intravenous fluids and effects of bumetanide.

Author: GlaserNicole, YuenNatalie, AndersonSteven E, TancrediDaniel J, O'DonnellMartha E

Improved cerebral metabolism
Reduced cerebral edema
Cerebral hypoperfusion
Reperfusion injury

Cerebral metabolism is compromised during DKA in juvenile rats, and further deteriorates during early DKA treatment. Bumetanide treatment may help diminish adverse effects of initial insulin/saline treatment.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, U.S. Gov't, Non-P.H.S.Research funding provided by US government agencies other than the Public Health Service.

Language : English

21.

Model-specific effects of bumetanide on epileptiform activity in the in-vitro intact hippocampus of the newborn mouse.

Author: KilbW, SinningA, LuhmannH J

Epilepsy treatment

This study investigated the effect of bumetanide on epileptiform activity in five different in-vitro epilepsy models using field potential recordings in the CA3 region of intact mouse hippocampal preparations. Bumetanide had diverse effects in different epilepsy models, suggesting that its mechanism of action is complex.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

22.

The effects of bumetanide on human umbilical artery contractions.

Author: DayiogluEmel, BuharaliogluC Kemal, SaracogluFerit, AkarFatma

Umbilical artery tone regulation

Bumetanide, an inhibitor of NKCC1, may play a role in the regulation of the umbilical artery tone.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

24.

Effects of amiloride and bumetanide on ion transport in the caecum of rabbit.

Author: Kosik-BogackaDanuta I, BanachBolesław, TyrakowskiTomasz, KozłowskaAlina, KozłowskaSylwia

Amiloride and bumetanide, blockers of sodium and chloride ion transport, were found to significantly reduce transepithelial electrical potential (PD) and transepithelial electrical potential difference (dPD) in isolated rabbit caecum fragments. This indicates that both ion transport pathways contribute to the induction of PD in the epithelium of the rabbit's caecum.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

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