The Pharmacokinetics of Bumetanide in the Newborn Infant

Lopez-Samblas, Ana M.; Adams, José A.; Goldberg, Ronald N.; Modi, Marlene

doi:10.1159/000244492

Cited by 40 publications

(32 citation statements)

References 11 publications

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“…44, 45, 51, 52 Although the TEAEs are in accord with well-described earlier reports, they stress the need to control electrolytes and hydration. There was no simple relation between TEAEs and efficacy.…”

Section: Discussionsupporting

confidence: 88%

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

et al. 2017

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In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl−)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3–11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2–18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily.

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Section: Discussionsupporting

confidence: 88%

“…These results confirm that the pharmacokinetic parameters of bumetanide 0.5 mg ml −1 solution in this pediatric population compares with those described in adults. 43, 44, 45, 46 …”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…[19] Bumetanide is an inhibitor of both NKCC isoforms (1 and 2), and is FDA approved and clinically in use as a diuretic in all age groups, including neonates, [20], [21] as NKCC2 is expressed in the renal tubule cells in the loop of Henle. However, NKCC2 is not expressed in the brain and hence bumetanide actions in neurons depend on the presence of NKCC1, which is broadly expressed throughout the body, including in neurons.…”

Section: Introductionmentioning

confidence: 99%

Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures

et al. 2013

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Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na+-K+-2 Cl− cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABAA receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in EGABA. Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures.

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“…Bumetanide has been extensively studied as a diuretic in human neonates (Lopez-Samblas et al, 1997; Sullivan et al, 1996). More recent experimental indicate that long-term suppression of NKCC1 activity and chronic KCC2 over-expression produce alterations in migration patterns of neocortical principal neurons and their dendritic length (Ge et al 2006; Cancedda et al, 2007; Wang and Kriegstein, 2008).…”

Section: Discussionmentioning

confidence: 99%

Differences in Cortical versus Subcortical GABAergic Signaling: A Candidate Mechanism of Electroclinical Uncoupling of Neonatal Seizures

Glykys

Dzhala

Kuchibhotla

et al. 2009

Neuron

144

195

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Electroclinical dissociation of neonatal seizures refers to electrographic seizure activity that is not clinically manifest. Dissociation increases after treatment with Phenobarbital, which increases the GABAA receptor (GABAAR) conductance. The effects of GABAAR activation depend on the intracellular Cl− concentration ([Cl−]i) that is determined by the inward Cl− transporter NKCC1 and the outward Cl− transporter KCC2. Differential maturation of Cl− transport observed in cortical vs. subcortical regions should alter the efficacy of GABA-mediated inhibition. In perinatal rat pups, most thalamic neurons maintained low [Cl−]i, and were inhibited by GABA. Phenobarbital suppressed thalamic seizure activity. Most neocortical neurons maintained higher [Cl−]i, and were excited by GABAAR activation. Phenobarbital had insignificant anticonvulsant responses in the neocortex until NKCC1 was blocked. Regional differences in the ontogeny of Cl− transport may thus explain why seizure activity in the cortex is not suppressed by anticonvulsants that block the transmission of seizure activity through subcortical networks.

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The Pharmacokinetics of Bumetanide in the Newborn Infant

Cited by 40 publications

References 11 publications

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

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

Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures

Differences in Cortical versus Subcortical GABAergic Signaling: A Candidate Mechanism of Electroclinical Uncoupling of Neonatal Seizures

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