Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain—A new treatment strategy for neonatal seizures? Article Swipe
Wiebke Theilmann
,
Claudia Brandt
,
Bettina Bohnhorst
,
Anne‐Mieke Winstroth
,
Anibh M. Das
,
Martina Gramer
,
Andi Kipper
,
Markus Kalesse
,
Wolfgang Löscher
·
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.1111/epi.16746
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.1111/epi.16746
Objectives The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ‐aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N , N ‐dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents. However, it is not known whether esterase activity in neonates is sufficient to hydrolyze ester prodrugs such as DIMAEB. Methods In the present study, we examined whether esterases in neonatal serum of healthy term infants are capable of hydrolyzing DIMAEB to bumetanide and whether this activity is different from the serum of adults. Furthermore, to extrapolate the findings to brain tissue, we performed experiments with brain tissue and serum of neonatal and adult rats. Results Serum from 1‐ to 2‐day‐old infants was capable of hydrolyzing DIMAEB to bumetanide at a rate similar to that of serum from adult individuals. Similarly, serum and brain tissue of neonatal rats rapidly hydrolyzed DIMAEB to bumetanide. Significance These data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add‐on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1111/epi.16746
- https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/epi.16746
- OA Status
- hybrid
- Cited By
- 6
- References
- 51
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3095430332
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W3095430332Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1111/epi.16746Digital Object Identifier
- Title
-
Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain—A new treatment strategy for neonatal seizures?Work title
- Type
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articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2020Year of publication
- Publication date
-
2020-11-02Full publication date if available
- Authors
-
Wiebke Theilmann, Claudia Brandt, Bettina Bohnhorst, Anne‐Mieke Winstroth, Anibh M. Das, Martina Gramer, Andi Kipper, Markus Kalesse, Wolfgang LöscherList of authors in order
- Landing page
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https://doi.org/10.1111/epi.16746Publisher landing page
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https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/epi.16746Direct link to full text PDF
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YesWhether a free full text is available
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-
hybridOpen access status per OpenAlex
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https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/epi.16746Direct OA link when available
- Concepts
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Bumetanide, Prodrug, Pharmacology, Phenobarbital, Chemistry, Anticonvulsant, Endocrinology, Internal medicine, Medicine, Biochemistry, Epilepsy, Ion transporter, Membrane, PsychiatryTop concepts (fields/topics) attached by OpenAlex
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6Total citation count in OpenAlex
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2023: 2, 2022: 2, 2021: 2Per-year citation counts (last 5 years)
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51Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.prerequisite | 231 |
| abstract_inverted_index.2‐day‐old | 193 |
| abstract_inverted_index.intracellular | 36 |
| abstract_inverted_index.phenobarbital | 32, 244 |
| abstract_inverted_index.pharmacotherapy | 255 |
| abstract_inverted_index.γ‐aminobutyric | 26 |
| abstract_inverted_index.‐dimethylaminoethyl | 86 |
| cited_by_percentile_year.max | 96 |
| cited_by_percentile_year.min | 93 |
| corresponding_author_ids | https://openalex.org/A5010235451 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 9 |
| corresponding_institution_ids | https://openalex.org/I189991 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.7400000095367432 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.6434024 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |