piperidines and Retinopathy-of-Prematurity

Hypoxia-inducible factors (HIF) play a fundamental role in retinal neovascularization (NV) induced by low oxygen tension. In the presence of oxygen, the HIF-α subunit becomes hydroxylated at specific prolyl residues by prolyl hydroxylases (PHD), which triggers HIF-α for degradation. In our present study, we examined the effect of R59949, the diacylglycerol kinase (DGK) inhibitor II, on the retinal NV and its potential mechanism in an oxygen-induced retinopathy (OIR) model. OIR model was induced by exposure of hyperoxia (75 % oxygen) to C57BL/6J mice from postnatal day 7 (P7) to P12 and then returned to room air. By intraperitoneal injection once a day (10 μg/g/day) from P12 to P17, R59949 not only effectively prevented pathologic NV but also preserved the astrocyte morphology. Furthermore, the expression of PHD-2 was upregulated and HIF-1α and vascular endothelial growth factor (VEGF) were downregulated in the retina of OIR mice following R59949 treatment. These findings suggested a potential possibility that R59949 suppressed retinal neovascular pathophysiology via PHD2/HIF-1α/VEGF pathway.

Topics: Animals; Astrocytes; Diacylglycerol Kinase; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Piperidines; Quinazolinones; Retina; Retinal Vessels; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

Retinopathy of prematurity (ROP) is a significant cause of childhood blindness.. The aim of this study is to determine the feasibility of remifentanil analgesia during laser treatment of ROP performed in the neonatal intensive care unit (NICU).. Remifentanil was infused continuously during the procedure starting with a dose of 0.2 µg/kg/min and increased gradually to 0.6 µg/kg/min to provide an adequate level of analgesia.. We enrolled 64 infants. Remifentanil was infused continuously at a mean rate of 0.4 ± 0.1 μg/kg/min. No major adverse effects were observed except in two patients with reversible bradycardia and hypotension. Premature infant pain profile (PIPP) scores revealed no pain. Patients with bronchopulmonary dysplasia had similar remifentanil dosage, intubation duration, and extubation time.. Remifentanil analgesia for ROP treatment performed in the NICU by pediatricians is a safe and effective modality. This modality offers a practical solution in hospitals without readily available pediatric anesthetists.

Topics: Analgesics, Opioid; Feasibility Studies; Female; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Laser Coagulation; Male; Pain Measurement; Piperidines; Remifentanil; Retinopathy of Prematurity

Retinopathy of prematurity adversely affects premature infants because of oxygen-induced damage of the immature retinal vasculature, resulting in pathological neovascularization (NV). Our pilot studies using the mouse model of oxygen-induced retinopathy (OIR) showed marked increases in angiogenic mediators, including endothelins and endothelin receptor (EDNR) A. We hypothesized that activation of the endothelin system via EDNRA plays a causal role in pathological angiogenesis and up-regulation of angiogenic mediators, including vascular endothelial growth factor A (VEGFA) in OIR. Mice were exposed to 75% oxygen from post-natal day P7 to P12, treated with either vehicle or EDNRA antagonist BQ-123 or EDNRB antagonist BQ-788 on P12, and kept at room air from P12 to P17 (ischemic phase). RT-PCR analysis revealed increased levels of EDN2 and EDNRA mRNA, and Western blot analysis revealed increased EDN2 expression during the ischemic phase. EDNRA inhibition significantly increased vessel sprouting, resulting in enhanced physiological angiogenesis and decreased pathological NV, whereas EDNRB inhibition modestly improved vascular repair. OIR triggered significant increases in VEGFA protein and mRNA for delta-like ligand 4, apelin, angiopoietin-2, and monocyte chemoattractant protein-1. BQ-123 treatment significantly reduced these alterations. EDN2 expression was localized to retinal glia and pathological NV tufts of the OIR retinas. EDN2 also induced VEGFA protein expression in cultured astrocytes. In conclusion, inhibition of the EDNRA during OIR suppresses pathological NV and promotes physiological angiogenesis.

Topics: Animals; Animals, Newborn; Astrocytes; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Mice; Oligopeptides; Peptides, Cyclic; Piperidines; Retina; Retinal Neovascularization; Retinopathy of Prematurity; Signal Transduction; Vascular Endothelial Growth Factor A

We tested the hypothesis that recombinant human VEGF-A165b and the serine arginine protein kinase (SRPK) inhibitor, SRPIN340, which controls splicing of the VEGF-A pre-mRNA, prevent neovascularization in a rodent model of retinopathy of prematurity (ROP).. In the 50/10 oxygen-induced retinopathy (50/10 OIR) model that exposes newborn rats to repeated cycles of 24 hours of 50% oxygen alternating with 24 hours of 10% oxygen, pups received intraocular injections of SRPIN340, vehicle, VEGF165b, anti-VEGF antibody, or saline. Whole mounts of retinas were prepared for isolectin immunohistochemistry, and preretinal or intravitreal neovascularization (PRNV) determined by clock hour analysis.. The anti-VEGF antibody (P < 0.04), rhVEGF165b (P < 0.001), and SRPIN340 (P < 0.05) significantly reduced PRNV compared with control eyes. SRPIN340 reduced the expression of proangiogenic VEGF165 without affecting VEGF165b expression.. These results suggest that splicing regulation through selective downregulation of proangiogenic VEGF isoforms (via SRPK1 inhibition) or competitive inhibition of VEGF signaling by rhVEGF165b has the potential to be an effective alternative to potential cyto- and neurotoxic anti-VEGF agents in the treatment of pathological neovascularization in the eye.

Topics: Animals; Blotting, Western; Cells, Cultured; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant, Newborn; Injections, Intraocular; Niacinamide; Piperidines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Retinal Neovascularization; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

Topics: Anesthetics, Dissociative; Conscious Sedation; Humans; Infant, Newborn; Ketamine; Piperidines; Remifentanil; Retinopathy of Prematurity

Preterm infants often require surgery. As experimental evidence suggests that premature infants may experience pain and this could even result in fatal complications, the anaesthesiologist must face problems related to lowbirth weight, high risk of hypothermia, concomitant pulmonary disease and metabolic and receptor immaturity. Recently remifentanil has been considered an optimal analgesic drug in a preterm infant undergoing mechanical ventilation and frequent surgical manoeuvres, but no clinical studies have been reported in the literature. The aim of our study was to evaluate the efficacy of a continuous intravenous infusion of remifentanil in premature infants undergoing laser therapy for retinopathy of prematurity (ROP).. Six premature infants with ROP were scheduled for laser therapy. The procedure was performed in the neonatal intensive care unit. Transcutaneous carbon dioxide, pulse oximetry, respiratory rate, ECG and noninvasive blood pressure were continuously monitored. Infusion of remifentanil started with a dose of 0.75-1 microg x kg-1x min-1, 1 h before surgery. A midazolam bolus dose (0.20 mg x kg-1) was administered and the remifentanil infusion was increased to 3-5 microg x kg-1x min-1 taking into account haemodynamic and respiratory changes or spontaneous movements.. Increased dosage was necessary only for 10 min during the procedure. No changes in temperature and ventilatory settings were observed and after 2 h from the surgical procedure the preterm infants were back to their preoperative status.. A continuous infusion of remifentanil allowed optimal control of surgical stress and a return to preoperative status and ventilatory settings without side-effects.

Topics: Anesthetics, Intravenous; Hemodynamics; Humans; Infant, Newborn; Infant, Premature; Infusions, Intravenous; Laser Therapy; Piperidines; Remifentanil; Respiration; Retinopathy of Prematurity; Time Factors; Treatment Outcome