M Dal Monte

Propranolol concentrations after oral administration in term and preterm neonates

Abstract Objective: While propranolol pharmacokinetics has been extensively studied in adults, this study reports the first evaluation of propranolol pharmacokinetics in term and preterm neonates. Methods: Propranolol concentrations were measured in four term and 32 preterm newborns treated with oral propranolol at the dose of 0.5 or 0.25 mg/kg every 6 h by serial dried blood spots. Results: The levels of propranolol, although with high inter-individual variability, were proportional with the administered dose. Pharmacokinetic parameters evaluated at the steady state in newborns treated with 0.5 mg/kg/6 h showed values of maximal (71.7 ± 29.8 ng/mL), minimal (42.2 ± 20.8 ng/mL) and average concentration (60.8 ± 25.0 ng/mL), time of maximal concentration (2.6 ± 0.9 h) and area under the time-concentration curve (364.7 ± 150.2 ng/mL/h) similar to those observed in adults. In both dosing groups, elimination half-life was significantly longer (14.9 ± 4.3 and 15.9 ± 6.1 h), and apparent total body clearance (27.2 ± 13.9 and 31.3 ± 13.3 mL/kg/min) lower than those reported in adults, suggesting a slower metabolism in newborns. No differences were observed between newborns with different gestational age or different sex. Conclusions: Neonates treated with propranolol-exhibited drug concentrations proportional with the dose, with significant long half-life.

Expression of substance P, neurokinin 1 receptors (NK1) and neurokinin 3 receptors in the developing mouse retina and in the retina of NK1 knockout mice.

To complete a series of studies on the expression of substance P and neurokinin receptors in mammalian retinas, we investigated the occurrence of these molecules in developing mouse retinas and in retinas of mice with genetic deletion of the neurokinin 1 receptor, the preferred substance P receptor. Using semi-quantitative reverse transcription-polymerase chain reaction, we measured detectable levels of the gamma isoform of preprotachykinin A (a substance P precursor) mRNA at postnatal day 4. Neurokinin 1 receptor and neurokinin 3 receptor mRNAs were also detected at postnatal day 4. While gamma preprotachykinin A and neurokinin 1 receptor mRNA levels significantly increased up to eye opening (postnatal day 11), neurokinin 3 receptor mRNA levels remained constant throughout development. Substance P, neurokinin 1 receptor and neurokinin 3 receptor immunoreactivities were present at postnatal day 5. Substance P was in amacrine cells, neurokinin 1 receptor in developing amacrine and bipolar cells and neurokinin 3 receptor in OFF-type cone bipolar cells. Interestingly, a transient increase in the density of neurokinin 1 receptor immunoreactive processes was observed at eye opening in lamina 3 of the inner plexiform layer, suggesting a role of substance P and neurokinin 1 receptor in this developmental phase. However, in neurokinin 1 receptor knockout retinas, besides a significant increase of the gamma preprotachykinin A mRNA levels, no major changes were detected: neurokinin 3 receptor mRNA levels as well as substance P and neurokinin 3 receptor immunostainings were similar to wild types. Together with previous studies, these observations indicate that there are major differences in neurokinin 1 receptor expression patterns among developing mammalian retinas. The observations in neurokinin 1 receptor knockout mice may not be applicable to rats or rabbits, and substance P and neurokinin 1 receptor may play different developmental roles in different species.

Genetic deletion of β1- and β2-adrenergic receptors rescues the retina from hypoxia-induced pathologic angiogenesis

Purpose To investigate the effects of β1‐ and β2‐adrenergic receptor (AR) deletion in the vascular retinal response to hypoxia, to confirm and expand the role of β1‐ and β2‐ARs in regulating retinal angiogenesis and to get insights into the role of β3‐ARs.

Aquaporin 4 is required to induce retinal angiogenesis in a mouse model of oxygen-induced retinopathy

Purpose Aquaporin 4 (AQP4) is the most abundant water channel in the retina and participates in the formation of blood‐retinal barrier (BRB). In several retinal pathologies accompanied by BRB dysfunction the expression of AQP4 is altered. In the present study, we investigated the effects of AQP4 deletion in the vascular retinal response to hypoxia.