{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:06:39Z","timestamp":1747184799234,"version":"3.40.5"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T00:00:00Z","timestamp":1604275200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["274\/15\u20101"],"award-info":[{"award-number":["274\/15\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of \u03b3\u2010aminobutyric 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 <jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2010dimethylaminoethyl 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Serum from 1\u2010 to 2\u2010day\u2010old 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>These data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add\u2010on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16746","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T02:38:27Z","timestamp":1604371107000},"page":"269-278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain\u2014A new treatment strategy for neonatal seizures?"],"prefix":"10.1111","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6856-1902","authenticated-orcid":false,"given":"Wiebke","family":"Theilmann","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Brandt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettina","family":"Bohnhorst","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Allergology and Neonatology Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne\u2010Mieke","family":"Winstroth","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Allergology and Neonatology Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anibh Martin","family":"Das","sequence":"additional","affiliation":[{"name":"Clinic for Pediatric Kidney, Liver and Metabolic Diseases Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Gramer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andi","family":"Kipper","sequence":"additional","affiliation":[{"name":"Institute for Organic Chemistry Leibniz Universit\u00e4t Hannover Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Kalesse","sequence":"additional","affiliation":[{"name":"Institute for Organic Chemistry Leibniz Universit\u00e4t Hannover Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9648-8973","authenticated-orcid":false,"given":"Wolfgang","family":"L\u00f6scher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,11,2]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_9_2_1","DOI":"10.1002\/ana.21167"},{"volume-title":"WHO Guidelines on neonatal seizures","author":"World Health Organization","key":"e_1_2_9_3_1"},{"key":"e_1_2_9_4_1","article-title":"The ILAE classification of seizures & the epilepsies: modification for seizures in the neonate. 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