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?

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.

Ultrasound assessment of gastric emptying time in preterm infants: A prospective observational study.

BACKGROUND: In paediatric anaesthesia, pre-operative fasting should be short to prevent discomfort, hunger, thirst and metabolic disorders. Current European guidelines recommend pre-operative fasting times of 4 h for breast milk and 6 h for formula milk in infants, whereas some national guidelines allow both until 4 h before anaesthesia. OBJECTIVE: We evaluated the gastric emptying times of preterm infants after breast milk and formula milk, hypothesising that the mean gastric emptying time would be less than 4 h. DESIGN: A prospective, observational, noninterventional cohort study. SETTING: Neonatal ICU of a university hospital from August to September 2017. PATIENTS: Twenty-two infants with a postmenstrual mean ±â€ŠSD (range) age of 35 ±â€Š2 (32 to 40) weeks were included. Based on their prescription plan, 10 infants received breast milk and 12 received formula milk with a total volume of 50 ±â€Š16 (24 to 70) ml. INTERVENTIONS: Gastric emptying was examined by sonographic measurements of the gastric antral area (GAA) before (FT0) and hourly after breast milk or formula milk feeding (FT1 to FT3). MAIN OUTCOME MEASURES: Estimated gastric emptying time after enteral feeding with breast milk and formula milk in preterm infants. RESULTS: The GAA of the preterm infants initially increased and subsequently decreased after feeding. GAA correlated significantly with fasting time (r = -0.53, P < 0.0001). At FT3 [199 ±â€Š16 (175 to 225) min], GAA was 0.57 (0.42 to 0.91) cm and showed no difference compared with FT0. Using a linear regression model, the calculated mean gastric emptying time was 218 min. CONCLUSION: The study shows that the mean gastric emptying time after enteral feeding with breast milk and formula milk is less than 4 h in preterm infants. These results support our current national fasting regimen of 4 h for any milk composition in infants before anaesthesia. TRIAL REGISTRATION: German registry of clinical studies (DRKS-ID: DRKS 00013893).