This is the first demonstration that β-AR blockade is protective against retinal angiogenesis and ameliorates BRB dysfunction in OIR. Although the relevance of these results to infant ROP is uncertain, the findings may help to establish potential pharmacologic targets based on β3-AR pharmacology.

ABSTRACT.Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birthweight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new antivasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterized for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO 2 regulate the normal or abnormal production of hypoxia-inducible factor 1 and vascular endothelial growth factors (VEGF), which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF-1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF-1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti-VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and b-adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single-nucleotide polymorphisms within the b-ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using b-blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP.Key words: erythropoietin -hypoxia-inducible factor 1 -insulin-like growth factor-1 -neovascularization -pathophysiology -placental growth factor -retinopathy of prematurity -vascular endothelial growth factor -b-adrenergic receptors Acta Ophthalmol. 2014: 92: 2-20

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07530.x Abstract Oxygen‐induced retinopathy (OIR) is a model for human retinopathy of prematurity. In mice with OIR, beta‐adrenergic receptor (β‐AR) blockade with propranolol has been shown to ameliorate different aspects of retinal dysfunction in response to hypoxia. In the present study, we used the OIR model to investigate the role of distinct β‐ARs on retinal proangiogenic factors, pathogenic neovascularization and electroretinographic responses. Our results demonstrate that β2‐AR blockade with ICI 118,551 decreases retinal levels of proangiogenic factors and reduces pathogenic neovascularization, whereas β1‐ and β3‐AR antagonists do not. Determination of retinal protein kinase A activity is indicative of the fact that β‐AR blockers are indeed effective at the receptor level. In addition, the specificity of ICI 118,551 on retinal angiogenesis has been demonstrated by the finding that in mouse retinal explants, β2‐AR silencing prevents ICI 118,551 effects on hypoxia‐induced vascular endothelial growth factor accumulation. In OIR mice, ICI 118,551 is effective in increasing electroretinographic responses suggesting that activation of β2‐ARs constitutes an important part of the retinal response to hypoxia. Lastly, immunohistochemical studies demonstrate that β2‐ARs are localized to several retinal cells, particularly to Müller cells suggesting the possibility that β2‐ARs play a role in regulating vascular endothelial growth factor production by these cells. The present results suggest that pathogenic angiogenesis, a key change in many hypoxic/ischemic vision‐threatening retinal diseases, depends at least in part on β2‐AR activity and indicate that β2‐AR blockade can be effective against retinal angiogenesis.

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SUMMARYPurpose: Therapeutic hypothermia has recently been introduced to treat term newborns with hypoxic-ischemic encephalopathy, of whom more than half have seizures. Phenobarbital is widely used to treat neonatal seizures, but it is unknown whether its pharmacokinetics is affected by hypothermia. We evaluated the influence of hypothermia on phenobarbital pharmacokinetics in asphyxiated newborns. Methods: Nineteen term asphyxiated newborns treated with mild whole body hypothermia, started within 6 h after birth and protracted for 72 h, received phenobarbital for clinical seizures. Treatment schedule consisted of a loading dose of 20 mg/kg, titrated to response, up to a maximum dose of 40 mg/kg, followed by a maintenance dose of 2.5 or 1.5 mg/kg every 12 h. Phenobarbital concentrations were measured on 28 dried blood spots in each newborn. Key Findings: Eighteen newborns showed plasma concentrations within the reference range after receiving a loading dose of 20 mg/kg. In the remaining newborn, who had received a loading dose of 35 mg/kg, phenobarbital concentrations exceeded the upper reference limit. Phenobarbital concentrations reached a virtual steady state in all newborns. Pharmacokinetic parameters were then calculated. Minimum and maximum concentration (24.7 ± 8.8 and 30.63 ± 10.3 mg/L), average plasma concentration (27.37 ± 9.4 mg/L), and half-life (173.9 ± 62.5 h) were considerably higher than reported in literature for normothermic newborns. Pharmacokinetic parameters did not differ significantly between infants receiving different maintenance doses. Significance: Phenobarbital administered to newborns under whole body hypothermia results in higher plasma concentrations and longer half-lives than expected in normothermic newborns.

SUMMARYPurpose: Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate. Methods: Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots. Results: Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time-concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital. Conclusion: Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.

Objective To investigate whether topiramate associated with mild or deep hypothermia in asphyxiated term infants is safe in relation to the short-term outcome.Study design We report on 27 consecutive asphyxiated newborns who were treated with whole body hypothermia and 27 additional consecutive newborns with hypothermia who were co-treated with oral topiramate, once a day for 3 consecutive days, at 2 different doses.Results Newborns were divided in 6 groups according to the depth of hypothermia and the association with higher or lower topiramate dosage. A statistical comparison of the groups identified some differences in biochemical and hemodynamic variables, but no adverse effects attributable to topiramate were detected. There were no statistically significant differences in the groups in short-term outcomes, survival rate at discharge, or incidence of pathologic brain magnetic resonance imaging. ConclusionAlthough the number of newborns in this study was limited, the short-term outcome and the safety data appear to support the evaluation of topiramate in clinical trials to explore its possible additive neuroprotective action. (J Pediatr 2010;157:361-6).See editorial, p 351 and related articles, p 367 and p 499 N eonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is one of the leading causes of cerebral palsy, the incidence of which has remained essentially unchanged in recent decades despite improvements in perinatal practice and neonatal care.1 Topiramate (TPM), an anticonvulsant agent widely used in adults and children, 2,3 has multiple mechanisms of action, including an inhibitory effect on glutamate receptors. TPM has neuroprotective properties against hypoxic ischemic brain damage, both in vitro and in animal models, and was included in neuroprotective strategies for ischemic stroke 4-11 and neonatal hypoxic-ischemic cerebral injury. 12Several studies have demonstrated the therapeutic effects of whole-body or selective head cooling to treat asphyxiated newborns. [13][14][15] Consequently, mild hypothermia is recommended for the treatment of moderate degrees of encephalopathy. 1 Deep hypothermia may also be safe and neuroprotective. 16 Although TPM logically would be expected to enhance the neuroprotective effects of hypothermia in HIE, no trial has tested this combination treatment.1 Hypothermia can reduce drug clearance, thereby affecting the pharmacokinetics of drugs. 17 In an earlier pilot study, we assessed the effects of mild or deep hypothermia on TPM pharmacokinetics in neonates with HIE. We observed a slow absorption and elimination of TPM. 18 We now report the safety profile of TPM in neonates treated with hypothermia in a retrospective comparison with newborns treated with hypothermia only. MethodsWe studied asphyxiated newborns admitted in 2 neonatal intensive care units