|
1
|
Xie Y, Zheng S, Yang H. New advances in pharmacological research for retinopathy of prematurity. Zhejiang Da Xue Xue Bao Yi Xue Ban 2025:1-11. [PMID: 40394926 DOI: 10.3724/zdxbyxb-2024-0216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease that threatens the vision of premature infants. Various novel drugs have demonstrated therapeutic potential for ROP by targeting signaling pathways associated with vascular endothelial growth factor (VEGF), including PI3K/AKT, hypoxia-inducible factor (HIF)-1α/VEGF, oxidative stress, tumor necrosis factor (TNF)-α, and Notch pathways. Propranolol, insulin-like growth factor-1, and celecoxib attenuate pathological neovascularization via the PI3K/AKT signaling pathway. Tripterine and melatonin inhibit retinal neovascularization by modulating the HIF-1α/VEGF signaling axis. Adiponectin mitigates oxidative stress damage and preserves endothelial function by enhancing endothelial nitric oxide synthase activity. Omega-3 polyunsaturated fatty acids suppress TNF-α-mediated inflammatory responses, modulate retinal development and angiogenesis, and reduce retinal neovascular lesions. The γ-secretase inhibitor DAPT blocks Notch signaling to suppress abnormal vascular proliferation. These agents exhibit synergistic multi-pathway anti-angiogenic effects in preclinical models and early-phase clinical trials, offering critical insights for advancing drug development and clinical translation in ROP management.
Collapse
Affiliation(s)
- Yanxi Xie
- Department of Ophthalmology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China.
| | - Suilian Zheng
- Department of Ophthalmology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China.
| | - Hui Yang
- Department of Ophthalmology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China.
| |
Collapse
|
|
2
|
Filippi L, Gulden S, Cammalleri M, Araimo G, Cavallaro G, Villamor E. Retinopathy of prematurity in the era of precision neonatology: from risk stratification to targeted therapies. World J Pediatr 2025:10.1007/s12519-025-00919-1. [PMID: 40380041 DOI: 10.1007/s12519-025-00919-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/19/2025]
Affiliation(s)
- Luca Filippi
- Department of Clinical and Experimental Medicine, Neonatology and Neonatal Intensive Care Unit, University of Pisa, Pisa, 56124, Italy
| | - Silvia Gulden
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy
| | | | - Gabriella Araimo
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy
| | - Giacomo Cavallaro
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy.
| | - Eduardo Villamor
- Division of Neonatology, MosaKids Children's Hospital, Maastricht University Medical Centre (MUMC+), Research Institute for Oncology and Reproduction (GROW), Maastricht University, P. Debyelaan 25, Maastricht, 6229HX, The Netherlands.
| |
Collapse
|
|
3
|
Gong J, Chan KS, Rajesh A, Droho S, Lavine JA. Adrb2 Expression in Ocular-Infiltrating Macrophages Is Necessary for Interleukin-6 Expression and Choroidal Neovascularization. Invest Ophthalmol Vis Sci 2025; 66:43. [PMID: 40434345 DOI: 10.1167/iovs.66.5.43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2025] Open
Abstract
Purpose Effective therapies for treatment resistant neovascular age-related macular degeneration (nAMD) remain an unmet need. Beta-adrenergic receptor (AR) blockers can decrease laser-induced choroidal neovascularization (CNV) size in mice. We have shown that monocyte-derived macrophages (MDMs) and interleukin-6 (IL-6) are necessary for beta-AR blockers to inhibit CNV. However, the specific beta-AR and the mechanism of this pathway are not fully elucidated. We hypothesized that beta2-AR (Adrb2) signaling on MDMs increases IL-6 production and stimulates CNV. Methods Previously published single-cell RNA-sequencing data was reanalyzed to determine which mononuclear phagocytes express beta-ARs. Adrb2flox/flox: Cx3cr1CreER/+ mice (Adrb2ΔMacs) or Adrb2flox/flox (Adrb2flox) controls were given tamoxifen injections at either four weeks before or at the time of laser-induced CNV to knockout Adrb2 in tissue resident or all macrophages, respectively. Mice underwent laser induced-CNV, and eyes were collected for choroidal wholemount immunofluorescence imaging to measure CNV area, multiparameter flow cytometry to analyze macrophage heterogeneity, and ELISAs to quantitate IL-6 levels. Results Adrb2 was the predominantly expressed beta-AR and was found on microglia, macrophages, and monocytes. Adrb2 deletion in tissue resident macrophages had no effect upon CNV area. Adrb2 deletion in all macrophages decreased CNV area by 1.4-fold. Adrb2ΔMacs posterior eye cups demonstrated similar levels of pro-angiogenic CD11c+ macrophages compared to Adrb2flox controls, but Ly6CnegCD11cneg macrophages were significantly increased. IL-6 levels increased with laser in Adrb2flox controls, but IL-6 levels in Adrb2ΔMacs posterior eye cups were unchanged. Conclusions Beta2-AR deletion in ocular-infiltrating macrophages decreases laser-induced CNV area. Beta2-AR expression regulates IL-6 expression in monocyte-derived macrophages.
Collapse
Affiliation(s)
- Joyce Gong
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Kyle S Chan
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Amrita Rajesh
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Steve Droho
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Jeremy A Lavine
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| |
Collapse
|
|
4
|
Bradley FE, Fernández Faith E, Shah SD, Braun M, Pope E, Lara-Corrales I, Witman PM, Harfmann K, Buros Stein A, Frieden IJ. A retrospective multicenter cohort study of differences in clinical characteristics of Infantile Hemangiomas in preterm and term infants: Prematurity increases risk of permanent cutaneous sequelae. J Am Acad Dermatol 2025; 92:546-553. [PMID: 39455031 DOI: 10.1016/j.jaad.2024.09.066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 08/21/2024] [Accepted: 09/04/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND We observed many preterm infants with unexpectedly thick infantile hemangiomas (IH), a subtype known to be associated with an increased risk of scarring. OBJECTIVE To cf the clinical features of localized IH in preterm vs term infants. METHODS A retrospective study was conducted at 3 tertiary referral centers involving 830 consecutive patients with localized IH. RESULTS Preterm infants had a significantly higher incidence of superficial IH (75% in <33 weeks, 57% in 33 to <37 weeks, and 50% in term infants, P = .007). Overall, their IH had thicker superficial components (P < .001) and more stepped borders (P < .001). These features correlated with the degree of prematurity. The average chronological age at presentation to the specialist was 5.6 (SD = 6.2) months, with no difference observed in gestational age. LIMITATIONS The retrospective design and use of nonstandardized clinical photographs. There may be biases introduced toward more severe IH types because the study sites were tertiary referral centers. CONCLUSIONS Preterm infants have features of IH that have obvious implications for systemic therapies. Most of these infants were seen beyond the typical proliferative phase when irreversible skin changes may have already occurred.
Collapse
Affiliation(s)
- Flora E Bradley
- Department of Dermatology, University of California, San Francisco School of Medicine, San Francisco, California.
| | - Esteban Fernández Faith
- Division of Dermatology, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio
| | - Sonal D Shah
- Department of Dermatology, University of California, San Francisco School of Medicine, San Francisco, California; Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Mitchell Braun
- Department of Dermatology, University of California, San Francisco School of Medicine, San Francisco, California
| | - Elena Pope
- Division of Pediatric Dermatology, The Hospital for Sick Children and University of Toronto, Toronto, Canada
| | - Irene Lara-Corrales
- Division of Pediatric Dermatology, The Hospital for Sick Children and University of Toronto, Toronto, Canada
| | - Patricia M Witman
- Division of Dermatology, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio
| | - Katya Harfmann
- Division of Dermatology, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio
| | | | - Ilona J Frieden
- Department of Dermatology, University of California, San Francisco School of Medicine, San Francisco, California
| |
Collapse
|
|
5
|
Ortiz-Seller A, Martorell P, Roselló P, Morcillo E, Ortiz JL. Comparison of Different Doses of Oral and Ocular Propranolol for Retinopathy of Prematurity: A Network Meta-Analysis. Paediatr Drugs 2024; 26:499-518. [PMID: 39112827 PMCID: PMC11335795 DOI: 10.1007/s40272-024-00647-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 08/22/2024]
Abstract
OBJECTIVE The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. METHODS Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose-response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). RESULTS Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2-3; S23) of ROP progression compared with its administration at earlier stages (stages 0-1; S01). OR values for oral propranolol 1.5 and 2 mg/kg/day given at S23 were 0.13 (95% CrI 0.04-0.37) and 0.16 (95% CrI 0.04-0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02-2.96) and 0.78 (95% CrI 0.14-4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09-1.00) versus an S01 OR of 0.64 (95% CrI 0.21-2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5-2 mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose-response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5 mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02-0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05-0.93) and laser (OR 0.16; 95% CrI 0.02-1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5-1.0 mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5 mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5 mg/kg/day and the highest risk difference for oral propranolol 2.0 mg/kg/day (0.06; 95% CI -0.01 to 0.13). CONCLUSION A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies.
Collapse
Affiliation(s)
- Amparo Ortiz-Seller
- Unit of Pediatric Ophthalmology and Strabismus, Oftalvist Clinic, Valencia, Spain
| | - Pablo Martorell
- Department of Chemical and Nuclear Engineering, Universitat Politècnica de València, Valencia, Spain
| | - Patricia Roselló
- Intensive Pediatric Care Unit, University Clinic Hospital of Valencia, Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Esteban Morcillo
- Health Research Institute (INCLIVA), Clinic University Hospital of Valencia, Valencia, Spain
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Av. Blasco Ibáñez 15, 46010, Valencia, Spain
| | - José L Ortiz
- Health Research Institute (INCLIVA), Clinic University Hospital of Valencia, Valencia, Spain.
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Av. Blasco Ibáñez 15, 46010, Valencia, Spain.
| |
Collapse
|
|
6
|
Scaramuzzo RT, Crucitta S, del Re M, Cammalleri M, Bagnoli P, Dal Monte M, Pini A, Filippi L. β3-adREnoceptor Analysis in CORD Blood of Neonates (β3 RECORD): Study Protocol of a Pilot Clinical Investigation. Life (Basel) 2024; 14:776. [PMID: 38929758 PMCID: PMC11204445 DOI: 10.3390/life14060776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/12/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Background and Objective: The embryo and the fetus develop in a physiologically hypoxic environment, where vascularization is sustained by HIF-1, VEGF, and the β-adrenergic system. In animals, β3-adrenoceptors (β3-ARs), up-regulated by hypoxia, favor global fetal wellness to such an extent that most diseases related to prematurity are hypothesized to be induced or aggravated by a precocious β3-AR down-regulation, due to premature exposure to a relatively hyperoxic environment. In animals, β3-AR pharmacological agonism is currently investigated as a possible new therapeutic opportunity to counteract oxygen-induced damages. Our goal is to translate the knowledge acquired in animals to humans. Recently, we have demonstrated that fetuses become progressively more hypoxemic from mid-gestation to near-term, but starting from the 33rd-34th week, oxygenation progressively increases until birth. The present paper aims to describe a clinical research protocol, evaluating whether the expression level of HIF-1, β3-ARs, and VEGF is modulated by oxygen during intrauterine and postnatal life, in a similar way to animals. Materials and Methods: In a prospective, non-profit, single-center observational study we will enroll 100 preterm (group A) and 100 full-term newborns (group B). We will collect cord blood samples (T0) and measure the RNA expression level of HIF-1, β3-ARs, and VEGF by digital PCR. In preterms, we will also measure gene expression at 48-72h (T1), 14 days (T2), and 30 days (T3) of life and at 40 ± 3 weeks of post-menstrual age (T4), regardless of the day of life. We will compare group A (T0) vs. group B (T0) and identify any correlations between the values obtained from serial samples in group A and the clinical data of the patients. Our protocol has been approved by the Pediatric Ethical Committee for Clinical Research of the Tuscany region (number 291/2022). Expected Results: The observation that in infants, the HIF-1/β3-ARs/VEGF axis shows similar modulation to that of animals could suggest that β3-ARs also promote fetal well-being in humans.
Collapse
Affiliation(s)
| | - Stefania Crucitta
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (S.C.); (M.d.R.)
| | - Marzia del Re
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (S.C.); (M.d.R.)
| | - Maurizio Cammalleri
- Unit of General Physiology, Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.C.); (P.B.); (M.D.M.)
| | - Paola Bagnoli
- Unit of General Physiology, Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.C.); (P.B.); (M.D.M.)
| | - Massimo Dal Monte
- Unit of General Physiology, Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.C.); (P.B.); (M.D.M.)
| | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy;
| | - Luca Filippi
- Neonatology Unit, Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, Italy
- Neonatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| |
Collapse
|
|
7
|
Cammalleri M, Filippi L, Dal Monte M, Bagnoli P. A promising case of preclinical-clinical translation: β-adrenoceptor blockade from the oxygen-induced retinopathy model to retinopathy of prematurity. Front Physiol 2024; 15:1408605. [PMID: 38938747 PMCID: PMC11208707 DOI: 10.3389/fphys.2024.1408605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/27/2024] [Indexed: 06/29/2024] Open
Abstract
Although compartmentalization of the eye seems to promote its experimental manipulation, drug penetration to its posterior part is severely limited by hard barriers thus hindering drug development for eye diseases. In particular, angiogenesis-related retinal diseases share common mechanisms and are responsible for the majority of cases of blindness. Their prevalence is globally increasing mostly because of the increased incidence of systemic pathologies in the adult. Despite the number of preclinical findings demonstrating the efficacy of novel treatments, therapy of retinal neovascular diseases still remains confined to intravitreal anti-vascular endothelial growth factor treatments with some extension to anti-inflammatory therapy. In the mare magnum of preclinical findings aimed to develop novel avenues for future therapies, most compounds, despite their efficacy in experimental models, do not seem to meet the criteria for their therapeutic application. In particular, the groove between preclinical findings and their clinical application increases instead of decreasing and the attempt to bridging the gap between them creates intense frustration and a sense of defeat. In this complex scenario, we will discuss here the role that overactivation of the sympathetic system plays in retinal vessel proliferation in response to hypoxia using the oxygen-induced retinopathy (OIR) model. The potential application of the beta-adrenoceptor (β-AR) blockade with propranolol to the treatment of retinopathy of prematurity will be also discussed in light of preclinical findings in the OIR model and clinical trials using propranolol in preterm infants either per os or as eye drops.
Collapse
Affiliation(s)
| | - Luca Filippi
- Neonatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy
| |
Collapse
|
|
8
|
Shafique MA, Haseeb A, Uddin MMN, Asghar B, Chaudhry ER, Raqib MA, Ali SMS, Mustafa MS. Effectiveness of Propranolol in Preventing Severe Retinopathy of Prematurity: A Comprehensive Systematic Review and Meta-Analysis. Am J Ophthalmol 2024; 259:141-150. [PMID: 37979602 DOI: 10.1016/j.ajo.2023.11.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 10/02/2023] [Accepted: 11/11/2023] [Indexed: 11/20/2023]
Abstract
PURPOSE To learn more about the effectiveness of oral propranolol as a therapeutic alternative for preterm newborns with pre-existing retinopathy of prematurity (ROP) as well as an early prevention method for ROP, one of the most common but avoidable causes of juvenile blindness. STUDY DESIGN Meta-analysis of relevant literature. METHODS A total of 3464 papers were identified, with 2873 from PubMed, 39 from Scopus, 67 from Medline, and 16 from Embase. After screening, finally, a total of 8 studies were deemed suitable for review. Following the PRISMA guidelines, published literature was systematically assessed up to May 10, 2023. Trials and observational studies were included in which beta blockage was used to prevent severe ROP (defined as stage ≥3 or requiring treatment). A total of 3646 papers were identified, with 2873 from PubMed, 39 from Scopus, 67 from Medline, and 16 from Embase. After screening, a total of 8 studies were deemed suitable for review. RESULTS The use of propranolol is linked to a lower risk of disease development in ROP compared to other therapies or control groups, according to the overall risk ratio of 0.59 (95% CI = 0.42, 0.82; P = .002, I2 = 41%). Additionally, the overall risk ratio for plus disease is 0.42 (95% CI = 0.23, 0.78; P = .006, I2 = 0%), for laser photocoagulation is 0.48 (95% CI = 0.31, 0.74; P = .001; I2 = 2%), and for intravitreal injection of VEGF is 0.43 (95% CI = 0.24, 0.74; P = 0.003, I2 = 0%), suggesting that use of propranolol may reduce the likelihood of developing a disease such as plus disease, requiring laser photocoagulation or necessitating intravitreal injection of vascular endothelial growth factor for ROP, respectively. No statistically significant heterogeneity was found in this study (P > .10, I2 = 50%). It can be concluded from this that the results of the chosen studies were sufficiently comparable and consistent. CONCLUSION This study showed that oral propranolol given as a preventive treatment in premature newborns successfully prevented severe ROP. Propranolol dosage and timing must now be carefully considered in the context of the study population, as these factors may have a major impact on the observed outcomes and treatment success.
Collapse
Affiliation(s)
- Muhammad Ashir Shafique
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Abdul Haseeb
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Muhammad Musab Nafees Uddin
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Bushra Asghar
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Eymaan Riaz Chaudhry
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Moosa Abdur Raqib
- Liaquat College of Medicine & Dentistry (M.A.R.), Karachi, Sindh, Pakistan
| | | | - Muhammad Saqlain Mustafa
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan.
| |
Collapse
|
|
9
|
Zhang L, Buonfiglio F, Fieß A, Pfeiffer N, Gericke A. Retinopathy of Prematurity-Targeting Hypoxic and Redox Signaling Pathways. Antioxidants (Basel) 2024; 13:148. [PMID: 38397746 PMCID: PMC10885953 DOI: 10.3390/antiox13020148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/19/2024] [Accepted: 01/21/2024] [Indexed: 02/25/2024] Open
Abstract
Retinopathy of prematurity (ROP) is a proliferative vascular ailment affecting the retina. It is the main risk factor for visual impairment and blindness in infants and young children worldwide. If left undiagnosed and untreated, it can progress to retinal detachment and severe visual impairment. Geographical variations in ROP epidemiology have emerged over recent decades, attributable to differing levels of care provided to preterm infants across countries and regions. Our understanding of the causes of ROP, screening, diagnosis, treatment, and associated risk factors continues to advance. This review article aims to present the pathophysiological mechanisms of ROP, including its treatment. Specifically, it delves into the latest cutting-edge treatment approaches targeting hypoxia and redox signaling pathways for this condition.
Collapse
Affiliation(s)
| | | | | | | | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (L.Z.); (F.B.); (A.F.); (N.P.)
| |
Collapse
|
|
10
|
Pascarella F, Scaramuzzo RT, Pini A, Cammalleri M, Bagnoli P, Ciantelli M, Filippi L. Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression. Front Pediatr 2024; 12:1322783. [PMID: 38292211 PMCID: PMC10824858 DOI: 10.3389/fped.2024.1322783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 01/04/2024] [Indexed: 02/01/2024] Open
Abstract
Despite the evident progress in neonatal medicine, retinopathy of prematurity (ROP) remains a serious threat to the vision of premature infants, due to a still partial understanding of the mechanisms underlying the development of this disease and the lack of drugs capable of arresting its progression. Although ROP is a multifactorial disease, retinal vascularization is strictly dependent on oxygen concentration. The exposition of the retina of a preterm newborn, still incompletely vascularized, to an atmosphere relatively hyperoxic, as the extrauterine environment, induces the downregulation of proangiogenic factors and therefore the interruption of vascularization (first ischemic phase of ROP). However, over the following weeks, the growing metabolic requirement of this ischemic retina produces a progressive hypoxia that specularly promotes the surge of proangiogenic factors, finally leading to proliferative retinopathy (second proliferative phase of ROP). The demonstration that the noradrenergic system is actively involved in the coupling between hypoxia and the induction of vasculogenesis paved the way for a pharmacologic intervention aimed at counteracting the interaction of noradrenaline with specific receptors and consequently the progression of ROP. A similar trend has been observed in infantile hemangiomas, the most common vascular lesion of childhood induced by pre-existing hypoxia, which shares similar characteristics with ROP. The fact that propranolol, an unselective antagonist of β1/2 adrenoceptors, counteracts the growth of infantile hemangiomas, suggested the idea of testing the efficacy of propranolol in infants with ROP. From preclinical studies, ongoing clinical trials demonstrated that topical administration of propranolol likely represents the optimal approach to reconcile its efficacy and maximum safety. Given the strict relationship between vessels and neurons, recovering retinal vascularization with propranolol may add further efficacy to prevent retinal dysfunction. In conclusion, the strategy of contrasting precociously the progression of the disease appears to be more advantageous than the current wait-and-see therapeutic approach, which instead is mainly focused on avoiding retinal detachment.
Collapse
Affiliation(s)
| | | | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maurizio Cammalleri
- Unit of General Physiology, Department of Biology, University of Pisa, Pisa, Italy
| | - Paola Bagnoli
- Unit of General Physiology, Department of Biology, University of Pisa, Pisa, Italy
| | | | - Luca Filippi
- Neonatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| |
Collapse
|
|
11
|
Scaramuzzo RT, Bagnoli P, Dal Monte M, Cammalleri M, Pini A, Ballini S, Bendinelli A, Desideri I, Ciantelli M, Filippi L. Treating infants with 0.2% propranolol eye micro-drops drastically reduced the progression of retinopathy of prematurity. Acta Paediatr 2023; 112:1905-1906. [PMID: 37199226 DOI: 10.1111/apa.16850] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/19/2023]
Affiliation(s)
| | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy
| | | | | | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Sandy Ballini
- Neonatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Anna Bendinelli
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Ielizza Desideri
- Hospital Pharmacy, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Luca Filippi
- Neonatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| |
Collapse
|
|
12
|
Fevereiro-Martins M, Marques-Neves C, Guimarães H, Bicho M. Retinopathy of prematurity: A review of pathophysiology and signaling pathways. Surv Ophthalmol 2023; 68:175-210. [PMID: 36427559 DOI: 10.1016/j.survophthal.2022.11.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina and a leading cause of visual impairment and childhood blindness worldwide. The disease is characterized by an early stage of retinal microvascular degeneration, followed by neovascularization that can lead to subsequent retinal detachment and permanent visual loss. Several factors play a key role during the different pathological stages of the disease. Oxidative and nitrosative stress and inflammatory processes are important contributors to the early stage of ROP. Nitric oxide synthase and arginase play important roles in ischemia/reperfusion-induced neurovascular degeneration. Destructive neovascularization is driven by mediators of the hypoxia-inducible factor pathway, such as vascular endothelial growth factor and metabolic factors (succinate). The extracellular matrix is involved in hypoxia-induced retinal neovascularization. Vasorepulsive molecules (semaphorin 3A) intervene preventing the revascularization of the avascular zone. This review focuses on current concepts about signaling pathways and their mediators, involved in the pathogenesis of ROP, highlighting new potentially preventive and therapeutic modalities. A better understanding of the intricate molecular mechanisms underlying the pathogenesis of ROP should allow the development of more effective and targeted therapeutic agents to reduce aberrant vasoproliferation and facilitate physiological retinal vascular development.
Collapse
Affiliation(s)
- Mariza Fevereiro-Martins
- Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal; Departamento de Oftalmologia, Hospital Cuf Descobertas, Lisboa, Portugal.
| | - Carlos Marques-Neves
- Centro de Estudos das Ci.¼ncias da Visão, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
| | - Hercília Guimarães
- Departamento de Ginecologia-Obstetrícia e Pediatria, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
| | - Manuel Bicho
- Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal.
| |
Collapse
|
|
13
|
Cammalleri M, Amato R, Dal Monte M, Filippi L, Bagnoli P. The β3 adrenoceptor in proliferative retinopathies: "Cinderella" steps out of its family shadow. Pharmacol Res 2023; 190:106713. [PMID: 36863427 DOI: 10.1016/j.phrs.2023.106713] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/14/2023] [Accepted: 02/27/2023] [Indexed: 03/04/2023]
Abstract
In the retina, hypoxic condition leads to overgrowing leaky vessels resulting in altered metabolic supply that may cause impaired visual function. Hypoxia-inducible factor-1 (HIF-1) is a central regulator of the retinal response to hypoxia by activating the transcription of numerous target genes, including vascular endothelium growth factor, which acts as a major player in retinal angiogenesis. In the present review, oxygen urge by the retina and its oxygen sensing systems including HIF-1 are discussed in respect to the role of the beta-adrenergic receptors (β-ARs) and their pharmacologic manipulation in the vascular response to hypoxia. In the β-AR family, β1- and β2-AR have long been attracting attention because their pharmacology is intensely used for human health, while β3-AR, the third and last cloned receptor is no longer increasingly emerging as an attractive target for drug discovery. Here, β3-AR, a main character in several organs including the heart, the adipose tissue and the urinary bladder, but so far a supporting actor in the retina, has been thoroughly examined in respect to its function in retinal response to hypoxia. In particular, its oxygen dependence has been taken as a key indicator of β3-AR involvement in HIF-1-mediated responses to oxygen. Hence, the possibility of β3-AR transcription by HIF-1 has been discussed from early circumstantial evidence to the recent demonstration that β3-AR acts as a novel HIF-1 target gene by playing like a putative intermediary between oxygen levels and retinal vessel proliferation. Thus, targeting β3-AR may implement the therapeutic armamentarium against neovascular pathologies of the eye.
Collapse
Affiliation(s)
| | - Rosario Amato
- Department of Biology, University of Pisa, Pisa, Italy
| | | | - Luca Filippi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy.
| |
Collapse
|
|
14
|
Abstract
PURPOSE OF REVIEW Incontinentia pigmenti (IP) is a rare X-linked dominant phakomatosis that predominately presents with dermatologic manifestations but can also cause central nervous system and ocular abnormalities. Awareness of the ocular complications of IP is crucial to identify ocular abnormalities early and prevent permanent vision loss. RECENT FINDINGS There have been significant recent advances in ocular diagnostic imaging in IP. Optical coherence tomography (OCT) has helped characterize outer plexiform layer abnormalities in the macula, which can help explain central vision loss in IP patients. OCT angiography (OCT-A) also identifies macular vascular changes that induce these foveal structural abnormalities and may supplement fluorescein angiography, the current standard of care to identify peripheral retinal ischemia and neovascularization for infants with IP. Additionally, recent studies have presented excellent anatomic outcomes years after laser photocoagulation to ischemic retina. Early data indicates that antivascular endothelial growth factor therapy can induce retinal revascularization, but runs the risk of late recurrent neovascularization and requires long-term monitoring. SUMMARY Ophthalmic imaging is evolving in the evaluation of IP and is increasingly guiding treatment modalities. A particular focus on the ocular manifestations of IP has been the ideal treatment for retinopathy in this disorder.
Collapse
|
|
15
|
Su S, Zou P, Yang G, Wang Y, Liu L, Liu Y, Zhang J, Ding Y. Propranolol ameliorates retinopathy of prematurity in mice by downregulating HIF-1α via the PI3K/Akt/ERK pathway. Pediatr Res 2022; 93:1250-1257. [PMID: 35986147 DOI: 10.1038/s41390-022-02211-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 06/13/2022] [Accepted: 06/28/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Retinopathy of prematurity (ROP) is the leading cause of blindness in infants, and elevation of HIF-1α through the PI3K/Akt and ERK pathways is implicated in ROP pathogenesis. The mechanism of action of propranolol in ROP remains controversial. We investigated the effect of propranolol on ROP and explored its potential mechanisms of action in an oxygen-induced retinopathy (OIR) mouse model. METHODS OIR mice were first treated with propranolol intraperitoneally, and the retina integrity was measured by FITC-dextran and hematoxylin-eosin staining. The expression of HIF-1α, VEGF, and key signaling pathway proteins was determined using real-time PCR and western blotting. RESULTS FITC-dextran staining showed that propranolol treatment reduced damage to retinal morphology in OIR mice. Mice treated with propranolol showed a reduced number of nuclei of vascular endothelial cells penetrating the inner limiting membrane of the retina, confirming the therapeutic effect of propranolol on ROP. Further analysis showed that HIF-1α and PI3K/Akt/ERK pathway protein levels were significantly elevated in OIR mice. In contrast, propranolol treatment downregulated the expression of these proteins, indicating that the PI3K/Akt/ERK/HIF-1α axis is associated with propranolol-induced ROP alleviation. CONCLUSIONS Propranolol has a therapeutic function against ROP, likely through the downregulation of HIF-1α via the PI3K/Akt/ERK pathway. IMPACT Propranolol can reduce the formation of abnormal retinal neovascularization in oxygen-induced retinopathy (OIR) models, and reduce leaking, tortuous, and abnormally expanding retinal blood vessels. Propranolol possibly improves OIR by inhibiting the activated ERK and HIF-1α pathways. Furthermore, propranolol may downregulate HIF-1α via the PI3K/Akt/ERK pathway to ameliorate retinopathy of prematurity. This study elucidated that the therapeutic effect of propranolol in OIR mice does not involve the VEGFR-2 pathway.
Collapse
Affiliation(s)
- Shaomin Su
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.,Department of Neonatology, Shenzhen Children's Hospital, Shenzhen, China
| | - Peicen Zou
- Department of Neonatology, Capital Institute of Pediatrics, Beijing, China
| | - Guangran Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yajuan Wang
- Department of Neonatology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China.
| | - Lei Liu
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Ying Liu
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Jinjing Zhang
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Yijun Ding
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| |
Collapse
|
|
16
|
Ryu J. New Aspects on the Treatment of Retinopathy of Prematurity: Currently Available Therapies and Emerging Novel Therapeutics. Int J Mol Sci 2022; 23:8529. [PMID: 35955664 PMCID: PMC9369302 DOI: 10.3390/ijms23158529] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 02/05/2023] Open
Abstract
Retinopathy of prematurity (ROP) is a rare proliferative ocular disorder in preterm infants. Because of the advancements in neonatal care, the incidence of ROP has increased gradually. Now, ROP is one of the leading causes of blindness in children. Preterm infants with immature retinal development are exposed to supplemental oxygen inside an incubator until their cardiopulmonary system is adequately developed. Once they are returned to room air, the relatively low oxygen level stimulates various angiogenesis factors initiating retinal neovascularization. If patients with ROP are not offered adequate and timely treatment, they can experience vision loss that may ultimately lead to permanent blindness. Although laser therapy and anti-vascular endothelial growth factor agents are widely used to treat ROP, they have limitations. Thus, it is important to identify novel therapeutics with minimal adverse effects for the treatment of ROP. To date, various pharmacologic and non-pharmacologic therapies have been assessed as treatments for ROP. In this review, the major molecular factors involved in the pathogenesis of ROP, currently offered therapies, therapies under investigation, and emerging novel therapeutics of ROP are discussed.
Collapse
Affiliation(s)
- Juhee Ryu
- Vessel-Organ Interaction Research Center, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea; ; Tel.: +82-539508583
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea
| |
Collapse
|
|
17
|
Dysregulated genomic and coding-transcriptomic factors in retinopathy of prematurity. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
18
|
Neurovascular abnormalities in retinopathy of prematurity and emerging therapies. J Mol Med (Berl) 2022; 100:817-828. [PMID: 35394143 DOI: 10.1007/s00109-022-02195-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/01/2022] [Accepted: 03/28/2022] [Indexed: 10/18/2022]
Abstract
Blood vessels in the developing retina are formed in concert with neural growth, resulting in functional neurovascular network. Disruption of the neurovascular coordination contributes to the pathogenesis of retinopathy of prematurity (ROP), a potentially blinding retinal neovascular disease in preterm infants that currently lacks an approved drug therapy in the USA. Despite vasculopathy as predominant clinical manifestations, an increasing number of studies revealed complex neurovascular interplays among neurons, glial cells and blood vessels during ROP. Coordinated expression of glia-derived vascular endothelial growth factor (VEGF) in spatio-temporal gradients is pivotal to the formation of well-organized vascular plexuses in the healthy retina, whereas uncoordinated VEGF expression triggers pathological angiogenesis with disorganized vascular tufts in ROP. In contrast with VEGF driving both pathological and physiological angiogenesis, neuron-derived angiogenic factor secretogranin III (Scg3) stringently regulates ROP but not healthy retinal vessels in animal models. Anti-VEGF and anti-Scg3 therapies confer similar high efficacies to alleviate ROP in preclinical studies but are distinct in their disease selectivity and safety. This review discusses neurovascular communication among retinal blood vessels, neurons and glial cells during retinal development and ROP pathogenesis and summarizes the current and emerging therapies to address unmet clinical needs for the disease.
Collapse
|
|
19
|
Filippi L, Cammalleri M, Amato R, Ciantelli M, Pini A, Bagnoli P, Dal Monte M. Decoupling Oxygen Tension From Retinal Vascularization as a New Perspective for Management of Retinopathy of Prematurity. New Opportunities From β-adrenoceptors. Front Pharmacol 2022; 13:835771. [PMID: 35126166 PMCID: PMC8814365 DOI: 10.3389/fphar.2022.835771] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/05/2022] [Indexed: 12/20/2022] Open
Abstract
Retinopathy of prematurity (ROP) is an evolutive and potentially blinding eye disease that affects preterm newborns. Unfortunately, until now no conservative therapy of active ROP with proven efficacy is available. Although ROP is a multifactorial disease, premature exposition to oxygen concentrations higher than those intrauterine, represents the initial pathogenetic trigger. The increase of oxygenation in a retina still incompletely vascularized promotes the downregulation of proangiogenic factors and finally the interruption of vascularization (ischemic phase). However, the increasing metabolic requirement of the ischemic retina induces, over the following weeks, a progressive hypoxia that specularly increases the levels of proangiogenic factors finally leading to proliferative retinopathy (proliferative phase). Considering non-modifiable the coupling between oxygen levels and vascularization, so far, neonatologists and ophthalmologists have "played defense", meticulously searching the minimum necessary concentration of oxygen for individual newborns, refining their diagnostic ability, adopting a careful monitoring policy, ready to decisively intervene only in a very advanced stage of disease progression. However, recent advances have demonstrated the possibility to pharmacologically modulate the relationship between oxygen and vascularization, opening thus the perspective for new therapeutic or preventive opportunities. The perspective of a shift from a defensive towards an attack strategy is now at hand.
Collapse
Affiliation(s)
- Luca Filippi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Rosario Amato
- Department of Biology, University of Pisa, Pisa, Italy
| | | | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy
| | | |
Collapse
|
|
20
|
Infantile hemangiomas β 3-adrenoceptor overexpression is associated with nonresponse to propranolol. Pediatr Res 2022; 91:163-170. [PMID: 33654276 DOI: 10.1038/s41390-021-01385-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 12/15/2020] [Accepted: 01/07/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Propranolol (antagonist of β1-/β2-AR but minimally active against β3-AR) is currently the first-line treatment for infantile hemangiomas (IH). Its efficacy is attributed to the blockade of β2-AR. However, its success rate is ~60%. Considering the growing interest in the angiogenic role of β3-ARs, we evaluated a possible relationship between β3-AR expression and response to propranolol. METHODS Fifteen samples of surgical biopsies were collected from patients with IH. Three were taken precociously from infants and then successfully treated with propranolol (responder group). Twelve were taken later, from residual lesions noncompletely responsive to propranolol (nonresponder group). A morphometrical analysis of the percentage of β1-, β2-, and β3-ARs positively stained area was compared between the two groups. RESULTS While no difference was found in both β1- and β2-AR expression level, a statistically significant increase of β3-AR positively stained area was observed in the nonresponder group. CONCLUSIONS Although the number of biopsies is insufficient to draw definitive conclusions, and the different β-AR pattern may be theoretically explained by the different timing of samplings, this study suggests a possible correlation between β3-AR expression and the reduced responsiveness to propranolol treatment. This study could pave the way for new therapeutic perspectives to manage IH. IMPACT Propranolol (unselective antagonist of β1 and β2-ARs) is currently the first-line treatment for IHs, with a success rate of ~60%. Its effectiveness has been attributed to its ability to block β2-ARs. However, β3-ARs (on which propranolol is minimally active) were significantly more expressed in hemangioma biopsies taken from patients nonresponsive to propranolol. This study suggests a possible role of β3-ARs in hemangioma pathogenesis and a possible new therapeutic target.
Collapse
|
|
21
|
Abstract
Retinopathy of prematurity (ROP) is an alteration in the development of the immature retina vascularization that frequently occurs in premature infants and is one of the leading causes of childhood blindness worldwide. In threshold stage retinopathy, laser photocoagulation is the standard treatment, particularly in those located in zone II. However, this therapy destroys parts of the retina and can lead to significant eye complications later in life. For this reason, in the last few years, antivascular endothelial growth factor agents are being used as monotherapy or as coadjuvant with laser, especially in retinopathy located in zone I. More recently, the administration of oral propranolol has been used as prevention and/or treatment of prethreshold retinopathy with encouraging results. This review provides an overview of the current evidence on newer treatment strategies for ROP. KEY POINTS: · Laser is the standard treatment in threshold retinopathy of prematurity (ROP).. · Prethreshold stages of the ROP have no treatment.. · Propranolol may prevent the progression of ROP..
Collapse
Affiliation(s)
- Aldo Bancalari
- Department of Pediatrics, Faculty of Medicine, University of Concepcion, Concepcion, Chile
| | - Ricardo Schade
- Ophthalmology Service, Guillermo Grant Benavente Hospital, Concepcion, Chile
| |
Collapse
|
|
22
|
Filippi L, Pini A, Cammalleri M, Bagnoli P, Dal Monte M. β3-Adrenoceptor, a novel player in the round-trip from neonatal diseases to cancer: Suggestive clues from embryo. Med Res Rev 2021; 42:1179-1201. [PMID: 34967048 PMCID: PMC9303287 DOI: 10.1002/med.21874] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 09/29/2021] [Accepted: 12/15/2021] [Indexed: 01/19/2023]
Abstract
The role of the β-adrenoceptors (β-ARs) in hypoxia-driven diseases has gained visibility after the demonstration that propranolol promotes the regression of infantile hemangiomas and ameliorates the signs of retinopathy of prematurity (ROP). Besides the role of β2-ARs, preclinical studies in ROP have also revealed that β3-ARs are upregulated by hypoxia and that they are possibly involved in retinal angiogenesis. In a sort of figurative round trip, peculiarities typical of ROP, where hypoxia drives retinal neovascularization, have been then translated to cancer, a disease equally characterized by hypoxia-driven angiogenesis. In this step, investigating the role of β3-ARs has taken advantage of the assumption that cancer growth uses a set of strategies in common with embryo development. The possibility that hypoxic induction of β3-ARs may represent one of the mechanisms through which primarily embryo (and then cancer, as an astute imitator) adapts to grow in an otherwise hostile environment, has grown evidence. In both cancer and embryo, β3-ARs exert similar functions by exploiting a metabolic shift known as the Warburg effect, by acquiring resistance against xenobiotics, and by inducing a local immune tolerance. An additional potential role of β3-AR as a marker of stemness has been suggested by the finding that its antagonism induces cancer cell differentiation evoking that β3-ARs may help cancer to grow in a nonhospital environment, a strategy also exploited by embryos. From cancer, the round trip goes back to neonatal diseases for which new possible interpretative keys and potential pharmacological perspectives have been suggested.
Collapse
Affiliation(s)
- Luca Filippi
- Department of Clinical and Experimental Medicine, Neonatology and Neonatal Intensive Care UnitUniversity of PisaPisaItaly
| | - Alessandro Pini
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Maurizio Cammalleri
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Paola Bagnoli
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Massimo Dal Monte
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| |
Collapse
|
|
23
|
Dai C, Webster KA, Bhatt A, Tian H, Su G, Li W. Concurrent Physiological and Pathological Angiogenesis in Retinopathy of Prematurity and Emerging Therapies. Int J Mol Sci 2021; 22:4809. [PMID: 34062733 PMCID: PMC8124946 DOI: 10.3390/ijms22094809] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 12/11/2022] Open
Abstract
Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and tortuous retinal blood vessels, and retinal or vitreous hemorrhages that may lead to retinal detachment, vision impairment and blindness. Compared with other neovascular diseases, ROP is unique because of ongoing and concurrent physiological and pathological angiogenesis in the developing retina. While the disease is currently treated by laser or cryotherapy, anti-vascular endothelial growth factor (VEGF) agents have been extensively investigated but are not approved in the U.S. because of safety concerns that they negatively interfere with physiological angiogenesis of the developing retina. An ideal therapeutic strategy would selectively inhibit pathological but not physiological angiogenesis. Our group recently described a novel strategy that selectively and safely alleviates pathological RNV in animal models of ROP by targeting secretogranin III (Scg3), a disease-restricted angiogenic factor. The preclinical profile of anti-Scg3 therapy presents a high potential for next-generation disease-targeted anti-angiogenic therapy for the ROP indication. This review focuses on retinal vessel development in neonates, the pathogenesis of ROP and its underlying molecular mechanisms, including different animal models, and provides a summary of current and emerging therapies.
Collapse
Affiliation(s)
- Chang Dai
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA; (C.D.); (K.A.W.); (A.B.)
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun 130041, China
| | - Keith A. Webster
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA; (C.D.); (K.A.W.); (A.B.)
- Department of Pharmacology, University of Miami School of Medicine, Miami, FL 33136, USA
- Everglades Biopharma, LLC, Houston, TX 77030, USA;
| | - Amit Bhatt
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA; (C.D.); (K.A.W.); (A.B.)
- Texas Children Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hong Tian
- Everglades Biopharma, LLC, Houston, TX 77030, USA;
| | - Guanfang Su
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun 130041, China
| | - Wei Li
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA; (C.D.); (K.A.W.); (A.B.)
| |
Collapse
|
|
24
|
Qadri A, Cai CL, Deslouches K, Siddiqui F, Aranda JV, Beharry KD. Ocular Versus Oral Propranolol for Prevention and/or Treatment of Oxygen-Induced Retinopathy in a Rat Model. J Ocul Pharmacol Ther 2021; 37:112-130. [PMID: 33535016 DOI: 10.1089/jop.2020.0092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Purpose: Propranolol, a nonselective B1/B2 adrenoceptor antagonist, promotes the regression of infantile hemangiomas likely through suppression of vascular endothelial growth factor (VEGF), which prompted its use for the prevention of retinopathy of prematurity. We tested the hypothesis that topical ocular propranolol is safe and effective for reducing the severity of oxygen-induced retinopathy (OIR) in the neonatal rat intermittent hypoxia (IH) model. Methods: At birth (P0), rat pups were randomly assigned to room air or neonatal intermittent hypoxia (IH) consisting of 50% O2 with brief episodes of hypoxia (12% O2) from P0 to P14, during which they received a single daily dose of oral propranolol (1 mg/kg/day in 50 μL in sterile normal saline) or topical ocular propranolol (0.2% in 10 μL in normal saline) from P5 to P14. Placebo-controlled littermates received 50 μL oral or 10 μL topical ocular sterile normal saline. Retinal vascular and astrocyte integrity; retinal histopathology and morphometry; and angiogenesis biomarkers were determined. Results: Topical ocular propranolol improved retinal vascular damage and preserved the astrocytic template, but did not completely prevent OIR. The beneficial effects of propranolol were associated with reduced ocular VEGF and increased endogenous soluble inhibitor, sVEGFR-1, when administered topically. Conclusions: Propranolol failed to completely prevent severe OIR, however, it prevented astrocyte degeneration resulting from neonatal IH-induced damage. We conclude that the mechanisms of propranolol's beneficial effects in neonatal IH may involve in part, astrocyte preservation.
Collapse
Affiliation(s)
- Areej Qadri
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA
| | - Charles L Cai
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA
| | - Karen Deslouches
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA
| | - Faisal Siddiqui
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA
| | - Jacob V Aranda
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA.,Department of Ophthalmology, Downstate Medical Center, State University of New York, Brooklyn, New York, USA.,State University of New York Eye Institute, New York, New York, USA
| | - Kay D Beharry
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA.,Department of Ophthalmology, Downstate Medical Center, State University of New York, Brooklyn, New York, USA.,State University of New York Eye Institute, New York, New York, USA
| |
Collapse
|
|
25
|
Arima M, Fujii Y, Sonoda KH. Translational Research in Retinopathy of Prematurity: From Bedside to Bench and Back Again. J Clin Med 2021; 10:331. [PMID: 33477419 PMCID: PMC7830975 DOI: 10.3390/jcm10020331] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/09/2021] [Accepted: 01/15/2021] [Indexed: 12/11/2022] Open
Abstract
Retinopathy of prematurity (ROP), a vascular proliferative disease affecting preterm infants, is a leading cause of childhood blindness. Various studies have investigated the pathogenesis of ROP. Clinical experience indicates that oxygen levels are strongly correlated with ROP development, which led to the development of oxygen-induced retinopathy (OIR) as an animal model of ROP. OIR has been used extensively to investigate the molecular mechanisms underlying ROP and to evaluate the efficacy of new drug candidates. Large clinical trials have demonstrated the efficacy of anti-vascular endothelial growth factor (VEGF) agents to treat ROP, and anti-VEGF therapy is presently becoming the first-line treatment worldwide. Anti-VEGF therapy has advantages over conventional treatments, including being minimally invasive with a low risk of refractive error. However, long-term safety concerns and the risk of late recurrence limit this treatment. There is an unmet medical need for novel ROP therapies, which need to be addressed by safe and minimally invasive therapies. The recent progress in biotechnology has contributed greatly to translational research. In this review, we outline how basic ROP research has evolved with clinical experience and the subsequent emergence of new drugs. We discuss previous and ongoing trials and present the candidate molecules expected to become novel targets.
Collapse
Affiliation(s)
- Mitsuru Arima
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
- Center for Clinical and Translational Research, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 8128582, Japan
| | - Yuya Fujii
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
| |
Collapse
|
|
26
|
Oranges T, El Hachem M, Filippeschi C, Romanelli M, Filippi L. The potential role of propranolol in incontinentia pigmenti. Dermatol Ther 2021; 34:e14737. [PMID: 33389807 DOI: 10.1111/dth.14737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/15/2020] [Accepted: 12/19/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Teresa Oranges
- Dermatology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.,Department of Dermatology, University of Pisa, Pisa, Italy
| | - May El Hachem
- Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Cesare Filippeschi
- Dermatology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy
| | | | - Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, Meyer Children's University Hospital, Florence, Italy
| |
Collapse
|
|
27
|
Kong HB, Zheng GY, He BM, Zhang Y, Zhou Q. Clinical Efficacy and Safety of Propranolol in the Prevention and Treatment of Retinopathy of Prematurity: A Meta-Analysis of Randomized Controlled Trials. Front Pediatr 2021; 9:631673. [PMID: 33643978 PMCID: PMC7902715 DOI: 10.3389/fped.2021.631673] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 01/04/2021] [Indexed: 12/22/2022] Open
Abstract
Objective: To perform a meta-analysis of randomized controlled trials verifying clinical efficacy and safety of propranolol in pre-term newborns with retinopathy of prematurity (ROP). Methods: We searched the literature databases (Pubmed, Embase, The Cochrane Library, Web of Science, CNKI, WanFang, VIP, CBM) for publications before August 10, 2020, and the World Health Organization's International Clinical Trials Registry and ClinicalTrials.gov for ongoing trials. Randomized controlled trials (RCTs) of propranolol for the prevention or treatment of ROP were included. The quality of the included studies was primarily assessed by the RCT tool of the Cochrane Collaboration. The included studies were quantified using a meta-analysis of relative risk (RR) estimated with a random effect model. Results: Our original search identified 171 articles, and five studies met our criteria. A meta-analysis was performed that showed that infants orally treated with propranolol had a decreased risk of disease progression: stage progression had an RR = 0.65 [95% confidence interval (CI), 0.47-0.88]), plus disease had an RR = 0.43 [95% CI, 0.22-0.82]. The demands for additional treatments had similar protective results: laser photocoagulations had an RR = 0.55 [95% CI, 0.35-0.86]), and intravitreal injection of anti-vascular endothelial growth factor had an RR = 0.45 [95% CI, 0.22-0.90]). The oral administration of propranolol was associated with an increased risk of adverse events (RR = 2.01 [95% CI, 1.02-3.97]). High-risk adverse events included bradycardia, hypotension, not gaining enough weight, bronchospasm, hypoglycemia, apnea, and increasing ventilator need. Subgroup analysis of ROP phases and stages found that the risk in stage 2 ROP of the second phase and the individual risk factors (stage progression, RR = 0.42 [95% CI, 0.27-0.65]; plus disease, RR = 0.40 [95% CI, 0.17-0.93]; laser photocoagulation, RR = 0.31 [95% CI, 0.14-0.68]) have statistically significant differences compared with other phases and stages. Conclusions: Pre-term newborns with ROP, especially in stage 2 ROP of the second phase, who were orally given propranolol have a reduced risk of disease progression and demand for additional treatments, but the safety needs more attention.
Collapse
Affiliation(s)
- Haibo B Kong
- Department of Pediatrics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Guoyuan Y Zheng
- Department of Neuroelectrophysiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Baomei M He
- Department of Pediatrics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ying Zhang
- Department of Pediatrics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qin Zhou
- Department of Pediatrics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| |
Collapse
|
|
28
|
Yang H, Hu DL, Xuan XX, Chen JJ, Xu S, Wu XJ, Zhang H, Shu Q, Guo XD. The efficacy and safety of treatments for infantile hemangiomas: a Bayesian network meta-analysis. Int J Dermatol 2020; 59:1320-1331. [PMID: 32662887 DOI: 10.1111/ijd.15015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/13/2020] [Accepted: 05/27/2020] [Indexed: 01/06/2023]
Abstract
Whether infantile hemangiomas (IHs) need to be treated and which treatment should be preferred are still controversial. We aimed to compare and rank the treatments and identify the optimal treatment for IHs. We searched PubMed, EMBASE, the Cochrane Library, Web of Science, and other sources for randomized controlled trials up to August 2019. We included trials comparingdifferent treatments and reported response or adverse events rate in IH patients. Two reviewers independently evaluated studies by specific criteria and extracted data. We assessed the risk of bias with the Cochrane risk of bias tool. Random-effects were performed for pair-to-pair and Bayesian framework network meta-analyses. The primary outcomes were efficacy and safety. We deemed 20 studies eligible, including 1149 participants and eight interventions. For efficacy, oral propranolol and topical propranolol/timolol were better than observation/placebo (OR, 95% CrI: 17.05, 4.02-94.94; 9.72, 1.91-59.08). For safety, topical propranolol/timolol was significantly better tolerated than oral propranolol (0.05, 0.001-0.66). Cluster analysis demonstrated oral propranolol was the most effective treatment for IHs, while topical propranolol/timolol showed high efficacy and the highest safety. Laser, intralesional propranolol or glucocorticoid, oral glucocorticoid, or captopril had significantly lower priority than oral propranolol or topical propranolol/timolol considering both efficacy and safety. The quality of evidence was rated as moderate or low in most comparisons. This network meta-analysis found topical beta-blockers had the potential to be the most preferable and beneficial option for IHs in consideration of both efficacy and safety.
Collapse
Affiliation(s)
- Hao Yang
- Zhejiang University School of Medicine, Hangzhou, China
- Department of Pediatric Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
- Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dong-Lai Hu
- Department of Pediatric Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| | - Xiao-Xiao Xuan
- Zhejiang University School of Medicine, Hangzhou, China
- Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Child Health, Hangzhou, China
| | - Jun-Jie Chen
- Department of Pediatric Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| | - Sheng Xu
- Department of Pediatric Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| | - Xiang-Jie Wu
- Department of Pediatric Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| | - Hang Zhang
- Zhejiang University School of Medicine, Hangzhou, China
- Department of Pediatric Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
- Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiang Shu
- Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Child Health, Hangzhou, China
| | - Xiao-Dong Guo
- Department of Pediatric Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| |
Collapse
|
|
29
|
Filippi L, Dal Monte M. A safety review of drugs used for the treatment of retinopathy of prematurity. Expert Opin Drug Saf 2020; 19:1409-1418. [PMID: 32954858 DOI: 10.1080/14740338.2020.1826927] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Retinopathy of Prematurity (ROP) is a sight-threatening disease representing one of the main disabling diseases affecting premature newborns. Presently, ROP is treated by surgical interventions and drug therapies are limited to the off-label use of a little amount of molecules approved for other pathologies. AREAS COVERED Many drugs that may potentially be used in treating ROP are recently proposed, in many cases after the demonstration of their effectiveness in preclinical studies. In this review, the authors discuss safety and effectiveness of the main proposed approaches in the pharmacologic treatment of the disease, including approaches based on oxygen therapy and nutritional interventions. EXPERT OPINION Surgical approaches to ROP are not without side effects. However, most of the proposed pharmacologic interventions can also raise specific concerns. In particular, these approaches follow a curative paradigm and are proposed in patients once the disease has progressed, with an effectiveness that is often smaller than expected. A goal in the treatment of ROP would be moving the paradigm toward a preventive approach that could be potentially effective in treating extremely low birth weight preterm infants before ROP becomes manifest.
Collapse
Affiliation(s)
- Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital , Florence, Italy
| | | |
Collapse
|
|
30
|
Baker JG, Fromont C, Bruder M, Thompson KSJ, Kellam B, Hill SJ, Gardiner SM, Fischer PM. Using Esterase Selectivity to Determine the In Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical β-Blockers. ACS Pharmacol Transl Sci 2020; 3:737-748. [PMID: 32832874 DOI: 10.1021/acsptsci.0c00051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Indexed: 11/30/2022]
Abstract
For disorders of the skin, eyes, ears, and respiratory tract, topical drugs, delivered directly to the target organ, are a therapeutic option. Compared with systemic oral therapy, the benefits of topical treatments include a faster onset of action, circumventing the liver first pass drug metabolism, and reducing systemic side effects. Nevertheless, some systemic absorption still occurs for many topical agents resulting in systemic side effects. One way to prevent these would be to develop drugs that are instantly degraded upon entry into the bloodstream by serum esterases. Because topical β-blockers are used in glaucoma and infantile hemeangioma and cause systemic side effects, the β-adrenoceptor system was used to test this hypothesis. Purified liver esterase reduced the apparent affinity of esmolol, an ester-containing β-blocker used in clinical emergencies, for the human β-adrenoceptors in a concentration and time-dependent manner. However, purified serum esterase had no effect on esmolol. Novel ester-containing β-blockers were synthesized and several were sensitive to both liver and serum esterases. Despite good in vitro affinity, one such compound, methyl 2-(3-chloro-4-(3-((2-(3-(3-chlorophenyl)ureido)ethyl)amino)-2-hydroxypropoxy)phenyl)acetate, had no effect on heart rate when injected intravenously into rats, even at 10 times the equipotent dose of esmolol and betaxolol that caused short and sustained reductions in heart rate, respectively. Thus, ester-based drugs, sensitive to serum esterases, offer a mechanism for developing topical agents that are truly devoid of systemic side effects. Furthermore, differential susceptibility to liver and serum esterases degradation may also allow the duration of systemic availability for other drugs to be fine-tuned.
Collapse
Affiliation(s)
- Jillian G Baker
- Cell Signalling Research Group, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, NG7 2RD, U.K.,Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, U.K
| | - Christophe Fromont
- School of Pharmacy and Centre for Biomedical Sciences, University of Nottingham, Nottingham, NG7 2RD, U.K
| | - Marjorie Bruder
- Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, U.K
| | - Kevin S J Thompson
- Cell Signalling Research Group, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, NG7 2RD, U.K
| | - Barrie Kellam
- Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, U.K.,School of Pharmacy and Centre for Biomedical Sciences, University of Nottingham, Nottingham, NG7 2RD, U.K
| | - Stephen J Hill
- Cell Signalling Research Group, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, NG7 2RD, U.K.,Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, U.K
| | - Sheila M Gardiner
- Cell Signalling Research Group, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, NG7 2RD, U.K
| | - Peter M Fischer
- Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, U.K.,School of Pharmacy and Centre for Biomedical Sciences, University of Nottingham, Nottingham, NG7 2RD, U.K
| |
Collapse
|
|
31
|
Droho S, Cuda CM, Perlman H, Lavine JA. Monocyte-Derived Macrophages Are Necessary for Beta-Adrenergic Receptor-Driven Choroidal Neovascularization Inhibition. Invest Ophthalmol Vis Sci 2020; 60:5059-5069. [PMID: 31800964 PMCID: PMC6894922 DOI: 10.1167/iovs.19-28165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Purpose Beta-adrenergic receptor (AR) antagonists, like propranolol, inhibit angiogenesis in multiple ocular conditions through an unknown mechanism. We previously showed that propranolol reduces choroidal neovascularization (CNV) by decreasing interleukin-6 levels. Since macrophages are one of the central producers of interleukin-6, we examined whether macrophages are required for propranolol-driven inhibition of choroidal angiogenesis. Methods We tested the anti-angiogenic properties of propranolol in the choroidal sprouting assay and the laser-induced CNV model. Bone marrow-derived monocytes (BMDMs) were added to the choroidal sprouting assay and Ccr2-/- mice were subjected to laser-induced CNV. Multi-parameter flow cytometry was performed to characterize the ocular mononuclear phagocyte populations after laser injury and during propranolol treatment. Results Propranolol reduced choroidal angiogenesis by 41% (P < 0.001) in the choroidal sprouting assay. Similarly, propranolol decreased laser-induced CNV by 50% (P < 0.05) in female mice, with no change in males. BMDMs increased choroidal sprouting by 146% (P < 0.0001), and this effect was ablated by propranolol. Beta-AR inhibition had no effect upon laser-induced CNV area in female Ccr2-/- mice. MHCII+ and MHCII- macrophages increased 20-fold following laser treatment in wildtype mice as compared to untreated mice, and this effect was completely attenuated in lasered Ccr2-/- mice. Moreover, propranolol increased the numbers of MHCII+ and MHCII- macrophages by 1.9 (P = 0.07) and 3.1 (P < 0.05) fold in lasered female mice with no change in macrophage numbers in males. Conclusions Our data suggest that propranolol inhibits angiogenesis through recruitment of monocyte-derived macrophages in female mice only. These data show the anti-angiogenic nature of beta-AR blocker-recruited monocyte-derived macrophages in CNV.
Collapse
Affiliation(s)
- Steven Droho
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Ilinois, United States
| | - Carla M Cuda
- Department of Medicine, Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Ilinois, United States
| | - Harris Perlman
- Department of Medicine, Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Ilinois, United States
| | - Jeremy A Lavine
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Ilinois, United States
| |
Collapse
|
|
32
|
Bastug O, Korkmaz L, Ozdemir A, Korkut S. Long- and short-term effects of propranolol hydrochloride treatment on very preterm newborns. J Clin Neonatol 2020. [DOI: 10.4103/jcn.jcn_28_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
33
|
Oral propranolol in prevention of severe retinopathy of prematurity: a systematic review and meta-analysis. J Perinatol 2019; 39:1584-1594. [PMID: 31570797 DOI: 10.1038/s41372-019-0503-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/10/2019] [Accepted: 07/31/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To systematically assess the efficacy of oral beta blockage treatment in primary (before established) and secondary (in threshold stages) prevention of severe retinopathy of prematurity (ROP) in premature infants born ≤32 weeks gestational age. STUDY DESIGN Following the PRISMA guidelines, published literature was systematically assessed up to April 27, 2018. Trials and observational studies, in which beta blockage was used to prevent severe ROP (defined as stage ≥3, or requiring treatment) were included. Meta-analyses including random effects models were conducted to determine the overall effect of oral beta blockage on prevention of ROP. RESULTS Six studies (five clinical trials and one observational study) including 461 infants met inclusion criteria using propranolol. The pooled relative risk (RR) of severe ROP in the primary and secondary prophylaxis groups were 0.65 (95% CI 0.43-0.98, NNT = 7) and 0.48 (95% CI 0.35-0.65, NNT = 6) in RCTs, respectively. The RR of severe ROP in one observational study was 0.21 (95% CI 0.08-0.55) with a NNT of 3. There were low heterogeneity and publication bias. Side effects occurred in 8.4% of participants on propranolol. CONCLUSIONS Systematic assessment of studies showed that prophylactic oral propranolol appeared to be effective in preventing severe ROP in premature infants ≤32 weeks gestational age. Additional well powered, multinational, randomized control trials reporting on long-term outcomes are needed.
Collapse
|
|
34
|
Abstract
With current screening for sight threatening retinopathy of prematurity (ROP) <10% of screened infants need treatment. Prediction models based on birth characteristics, postnatal weight gain and other factors have been developed to reduce examinations in low-risk infants. A model based on advanced statistics using data from >7000 infants registered in the Swedish ROP registry is being developed. Based on birth characteristics only, it appears to predict total risk of ROP-treatment as well as models including weight measurements. Treatment risk peaked at 12 weeks of age. Laser therapy is the method of choice for severe ROP. Anti-VEGF therapies are implemented worldwide despite insufficient knowledge of choice of drug, dosage and long term systemic effects. Prevention of ROP may be achieved through oxygen control and provision of the mother's breastmilk. Other interventions such as supplementation with long chain polyunsaturated fatty acids and preservation of fetal haemoglobin are investigated.
Collapse
|
|
35
|
Aranda JV, Qu J, Valencia GB, Beharry KD. Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity. Semin Perinatol 2019; 43:360-366. [PMID: 31153620 DOI: 10.1053/j.semperi.2019.05.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Retinopathy of Prematurity (ROP) is a preventable neovascular retinal disease with a lifetime impact on vision and ocular morbidities. Retinal vessel immaturity and oxygen therapy, influenced or modulated by several risk factors including oxidative stress, intermittent hypoxia and desaturations, inflammation, infection, malnutrition, retinal growth factor deficiencies or excesses, and others are determinant factors of pathologic retinal angiogenesis and ROP. These factors are pharmacologic targets for prevention and/or rescue therapy. These drugs, include intravitreal anti-vascular endothelial growth factor drugs, erythropoietin, ocular propranolol, caffeine, antioxidants, insulin-like growth factor-I, and omega 3 poly-unsaturated fatty acids, and are promising therapies to prevent ROP, but require further studies. Topical ocular non-steroidal anti-inflammatory drugs (NSAIDs) target inflammatory cascade but the best, safest, and most effective ocular NSAID and formulation remain to be developed. Timing of drug intervention appears critical. Moreover, the complex interactions of the various pathophysiologic mechanisms resulting in aberrant angiogenesis thence ROP strongly suggest that drug combinations and synergisms may be required for effective prevention of ROP and a lifetime of blindness.
Collapse
Affiliation(s)
- Jacob V Aranda
- Department of Pediatrics, Division of Neonsatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States; State University of New York Eye Institute, New York, NY 10075, United States.
| | - Jun Qu
- State University of New York Eye Institute, New York, NY 10075, United States; Department of Pharmaceutical Sciences, State University of New York in Buffalo, Buffalo, NY, United States
| | - Gloria B Valencia
- Department of Pediatrics, Division of Neonsatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Kay D Beharry
- Department of Pediatrics, Division of Neonsatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States; State University of New York Eye Institute, New York, NY 10075, United States
| |
Collapse
|
|
36
|
Du Y, He Y, Wang YL, Zhou JG, Chen C. The efficacy and safety of inositol supplementation in preterm infants to prevent retinopathy of prematurity: a systematic review and meta-analysis. BMC Ophthalmol 2019; 19:135. [PMID: 31238915 PMCID: PMC6593579 DOI: 10.1186/s12886-019-1140-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 06/04/2019] [Indexed: 11/29/2022] Open
Abstract
Background Inositol supplementation has been linked to beneficial effects on reducing the incidence of retinopathy of prematurity (ROP); however, it’s controversial. The meta-analysis aimed to check out the efficacy and safety of inositol supplementation in preterm infants for preventing ROP. Methods We conducted searches through PubMed, EMBASE, Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ClinicalTrials.gov website and conference proceedings. Randomized controlled trials comparing inositol supplementation with placebo were included. Two independent reviewers performed screening, review, and extraction. Statistical analysis was performed using R Project. Results Six studies (1194 infants) were proved eligible. In comparison with placebo, inositol supplementation revealed no effect on the incidence of severe ROP (relative risk [RR] = 0.49, 95% confidence interval [CI], 0.18–1.32; heterogeneity, P = .02; I2 = 66%; low quality of evidence [QOE]), mortality (RR = 1.25, 95% CI, 0.82–1.90; heterogeneity, P = .07; I2 = 51%; low QOE), all stages of ROP (RR = 0.98, 95% CI, 0.87–1.11; heterogeneity, P = .41; I2 = 0%; moderate QOE) and other adverse events. Sensitivity analysis showed an increased mortality in the inositol group (RR = 1.55, 95% CI, 1.14–2.11; heterogeneity, P = .30; I2 = 18%) after removing the study Hallman 1986, and meta-regression showed a significant association between publication year and efficacy of inositol compared with placebo (β = 0.1241; 95% CI, 0.0417–0.0026; z = 2.9527; p = .0032). Conclusions Based on current evidence, inositol supplementation showed no significant effect on preventing severe ROP, and exploratory sensitivity analysis showed a trend toward an increase on mortality. Electronic supplementary material The online version of this article (10.1186/s12886-019-1140-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Yang Du
- Department of Neonatology, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Yue He
- Department of Neonatology, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Yue-Lin Wang
- Department of Ophthalmology, Peking Union Medical College Hospital, Beijing, China
| | - Jian-Guo Zhou
- Department of Neonatology, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Chao Chen
- Department of Neonatology, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China.
| |
Collapse
|
|
37
|
Filippi L, Cavallaro G, Berti E, Padrini L, Araimo G, Regiroli G, Raffaeli G, Bozzetti V, Tagliabue P, Tomasini B, Mori A, Buonocore G, Agosti M, Bossi A, Chirico G, Aversa S, Fortunato P, Osnaghi S, Cavallotti B, Suzani M, Vanni M, Borsari G, Donati S, Nascimbeni G, Nardo D, Piermarocchi S, la Marca G, Forni G, Milani S, Cortinovis I, Calvani M, Bagnoli P, Dal Monte M, Calvani AM, Pugi A, Villamor E, Donzelli G, Mosca F. Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study. Front Pediatr 2019; 7:180. [PMID: 31134171 PMCID: PMC6514240 DOI: 10.3389/fped.2019.00180] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 04/18/2019] [Indexed: 12/21/2022] Open
Abstract
Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a β-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.
Collapse
Affiliation(s)
- Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Giacomo Cavallaro
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Elettra Berti
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Letizia Padrini
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Gabriella Araimo
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giulia Regiroli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Genny Raffaeli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Valentina Bozzetti
- Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy
| | - Paolo Tagliabue
- Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy
| | - Barbara Tomasini
- Neonatal Intensive Care Unit, University Hospital of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy
| | - Annalisa Mori
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Giuseppe Buonocore
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Massimo Agosti
- Neonatal Intensive Care Unit, Del Ponte Hospital, Varese, Italy
| | - Angela Bossi
- Neonatal Intensive Care Unit, Del Ponte Hospital, Varese, Italy
| | - Gaetano Chirico
- Neonatal Intensive Care Unit, Children's Hospital, University Hospital "Spedali Civili" of Brescia, Brescia, Italy
| | - Salvatore Aversa
- Neonatal Intensive Care Unit, Children's Hospital, University Hospital "Spedali Civili" of Brescia, Brescia, Italy
| | - Pina Fortunato
- Pediatric Ophthalmology, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Silvia Osnaghi
- Department of Ophthalmology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milan, Milan, Italy
| | - Barbara Cavallotti
- Department of Ophthalmology, ASST Monza, San Gerardo Hospital, Monza, Italy
| | - Martina Suzani
- Department of Ophthalmology, ASST Monza, San Gerardo Hospital, Monza, Italy
| | - Maurizio Vanni
- Pediatric Ophthalmology, University Hospital of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy
| | - Giulia Borsari
- Pediatric Ophthalmology, University Hospital of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy
| | - Simone Donati
- Department of Surgical and Morphological Sciences, Section of Ophthalmology, University of Insubria, Varese, Italy
| | - Giuseppe Nascimbeni
- Department of Ophthalmology, University Hospital "Spedali Civili" of Brescia, Brescia, Italy
| | - Daniel Nardo
- Department of Women's and Children's Health, Azienda Ospedaliera di Padova, University of Padua, Padua, Italy
| | | | - Giancarlo la Marca
- Newborn Screening, Biochemistry and Pharmacology Laboratory, Meyer Children's University Hospital, Florence, Italy
| | - Giulia Forni
- Newborn Screening, Biochemistry and Pharmacology Laboratory, Meyer Children's University Hospital, Florence, Italy
| | - Silvano Milani
- Laboratory "G.A. Maccacro," Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Ivan Cortinovis
- Laboratory "G.A. Maccacro," Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Maura Calvani
- Oncohematology Unit, Department of Pediatric Oncology, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Paola Bagnoli
- Department of Biology, Unit of General Physiology, University of Pisa, Pisa, Italy
| | - Massimo Dal Monte
- Department of Biology, Unit of General Physiology, University of Pisa, Pisa, Italy
| | - Anna Maria Calvani
- Department of Pharmacy, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Alessandra Pugi
- Clinical Trial Office, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Eduardo Villamor
- Department of Pediatrics, Maastricht University Medical Center, School for Oncology and Developmental Biology, Maastricht, Netherlands
| | - Gianpaolo Donzelli
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Fabio Mosca
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| |
Collapse
|
|
38
|
Elmasry K, Ibrahim AS, Abdulmoneim S, Al-Shabrawey M. Bioactive lipids and pathological retinal angiogenesis. Br J Pharmacol 2019; 176:93-109. [PMID: 30276789 PMCID: PMC6284336 DOI: 10.1111/bph.14507] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 08/14/2018] [Accepted: 08/22/2018] [Indexed: 12/22/2022] Open
Abstract
Angiogenesis, disruption of the retinal barrier, leukocyte-adhesion and oedema are cardinal signs of proliferative retinopathies that are associated with vision loss. Therefore, identifying factors that regulate these vascular dysfunctions is critical to target pathological angiogenesis. Given the conflicting role of bioactive lipids reported in the current literature, the goal of this review is to provide the reader a clear road map of what has been accomplished so far in the field with specific focus on the role of polyunsaturated fatty acids (PUFAs)-derived metabolites in proliferative retinopathies. This necessarily entails a description of the different retina cells, blood retina barriers and the role of (PUFAs)-derived metabolites in diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration as the most common types of proliferative retinopathies.
Collapse
Affiliation(s)
- Khaled Elmasry
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA
- Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Schepens Eye Research Institute/Massachusetts Eye and Ear & Department of ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Ahmed S Ibrahim
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA
| | - Samer Abdulmoneim
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA
- Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA
| | - Mohamed Al-Shabrawey
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA
- Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Department of Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA
| |
Collapse
|
|
39
|
Filippi L, Cavallaro G, Perciasepe L, Sandini E, Araimo G, Regiroli G, Raffaeli G, Bagnoli P, Dal Monte M, Calvani M, Fortunato P, Osnaghi S, De Masi S, Mosca F. Refractive Outcome in Preterm Newborns With ROP After Propranolol Treatment. A Retrospective Observational Cohort Study. Front Pediatr 2019; 7:479. [PMID: 31799228 PMCID: PMC6863805 DOI: 10.3389/fped.2019.00479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 10/30/2019] [Indexed: 11/13/2022] Open
Abstract
Background: Recent explorative studies suggest that propranolol reduces retinopathy of prematurity (ROP) progression, but the short-term effects of propranolol treatment at 1 year of corrected age have not been extensively evaluated. Methods: A multi-center retrospective observational cohort study was conducted to assess the physical development and the refractive outcome of infants with prior ROP treated with propranolol. Forty-nine infants treated with propranolol were compared with an equal number of patients who did not receive any propranolol therapy and represent the control group, with comparable anthropometrical characteristics and stages of ROP. Results: The weight, length, and head circumference at 1 year of corrected age were similar between infants who had been treated, or not, with propranolol, without any statistically significant differences. Refractive evaluation at 1 year showed spherical equivalent values decreasing with the progression of ROP toward more severe stages of the disease, together with an increasing number of infants with severe myopia. On the contrary, no differences were observed between infants who had been treated with propranolol and those who had not. Conclusion: This study confirms that the progression of ROP induces an increase of refractive errors and suggests that propranolol itself does not affect the refractive outcome. Therefore, if the efficacy of propranolol in counteracting ROP progression is confirmed by further clinical trials, the conclusion will be that propranolol might indirectly improve the visual outcome, reducing the progression of ROP.
Collapse
Affiliation(s)
- Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Giacomo Cavallaro
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Lavinia Perciasepe
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Elena Sandini
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Gabriella Araimo
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giulia Regiroli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Genny Raffaeli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paola Bagnoli
- Unit of General Physiology, Department of Biology, University of Pisa, Pisa, Italy
| | - Massimo Dal Monte
- Unit of General Physiology, Department of Biology, University of Pisa, Pisa, Italy
| | - Maura Calvani
- Oncohematology Unit, Department of Pediatric Oncology, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Pina Fortunato
- Pediatric Ophthalmology, A. Meyer" University Children's Hospital, Florence, Italy
| | - Silvia Osnaghi
- Department of Ophthalmology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Salvatore De Masi
- Clinical Trial Office, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Fabio Mosca
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| |
Collapse
|
|
40
|
Filippi L, de Libero C, Zamma Gallarati B, Fortunato P, Piozzi E. Propranolol eye drops in patients with corneal neovascularization. Medicine (Baltimore) 2018; 97:e13002. [PMID: 30407290 PMCID: PMC6250516 DOI: 10.1097/md.0000000000013002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
RATIONALE Studies performed in animal models of corneal neovascularization suggested the possible efficacy of a treatment with propranolol. Corneal neovascularization is one of the most feared complications of Stevens-Johnson syndrome that frequently involves ocular surface. We report the first 2 patients with severe ocular neo-vascularization treated with different degrees of success, with propranolol eye drops. PATIENT CONCERNS Two patients with corneal neovascularization complicating the Stevens-Johnson syndrome, not responsive to steroids and cyclosporine, were treated with propranolol eye drops. DIAGNOSES Corneal neovascularization was detected by ophthalmoscopic evaluation. INTERVENTIONS Topical treatment with propranolol eye drops at different concentrations. OUTCOMES Both patients reported dramatic subjective benefits (reduction of photophobia and discomfort) without adverse effects, and in the patient with a less advanced disease, an objective reduction of neovascularization and an improved visual acuity was observed. LESSONS This experience suggests that propranolol might be an inexpensive, safe and effective treatment in counteracting the progression of corneal neovascularization.
Collapse
Affiliation(s)
- Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department
| | - Cinzia de Libero
- Pediatric Ophthalmology Unit, “A. Meyer” University Children's Hospital, Florence
| | | | - Pina Fortunato
- Pediatric Ophthalmology Unit, “A. Meyer” University Children's Hospital, Florence
| | - Elena Piozzi
- Pediatric Ophthalmology Unit, Niguarda Ca’ Granda Metropolitan Hospital, Milan, Italy
| |
Collapse
|
|
41
|
Bührer C, Erdeve Ö, Bassler D, Bar-Oz B. Oral propranolol for prevention of threshold retinopathy of prematurity (ROPROP): protocol of a randomised controlled trial. BMJ Open 2018; 8:e021749. [PMID: 29982217 PMCID: PMC6042594 DOI: 10.1136/bmjopen-2018-021749] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Retinopathy of prematurity (ROP) is a disease observed in extremely premature infants characterised by visioning-threatening retinal vessel proliferation. Propranolol, a drug used for decades in newborn infants with heart diseases, hypertension and thyrotoxicosis and licenced for infantile haemangiomas, may be effective in halting progression of ROP to severe stages, as suggested by preliminary data from small studies. METHODS AND ANALYSIS ROPROP is an investigator-initiated, multicentre, placebo-controlled double-blind, randomised controlled trial aiming to assess the safety and efficacy of orally administered propranolol to reduce the risk of threshold ROP (stage 3) in extremely preterm infants at 48 weeks postmenstrual age (primary objective) and the rate of infants requiring local interventions for severe ROP (secondary objective). Key inclusion criteria: gestational age <28 weeks, birth weight <1250 g, postmenstrual age ≥31 and <37 weeks, incipient ROP (stage 1 or 2, with or without plus disease) and written informed consent by parents or legal guardian. Key exclusion criteria: requirement for open-label propranolol treatment, major congenital malformations (including those with cerebrovascular malformations), known chromosomal anomalies, colobomas and other eye malformations, atrioventricular block grade 2 or 3 and comedication with antiarrhythmics, clonidine, insulin (pharmacodynamic interaction), phenobarbital or rifampicin (pharmacokinetic interaction). The intervention consists of oral propranolol-hydrochloride (1.6 mg/kg/day in three to four divided dosages) or placebo until discharge, for a maximum of 10 weeks. Analysis is by intention to treat. ETHICS AND DISSEMINATION The protocol has received ethical and regulatory approval. Results will be published after peer review irrespective of the study outcome. TRIAL REGISTRATION NUMBERS NCT03083431 , EudraCT# 2017-002124-24 (EUCTR), 00013730 (DRKS); Pre-results.
Collapse
Affiliation(s)
- Christoph Bührer
- Department of Neonatology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Ömer Erdeve
- Division of Neonatology, Ankara University School of Medicine Children’s Hospital, Ankara, Turkey
| | - Dirk Bassler
- Department of Neonatology, Universitätsspital Zürich, Zurich, Switzerland
| | - Benjamin Bar-Oz
- Department of Neonatology, Hadassah Medical Center, Jerusalem, Israel
| |
Collapse
|
|
42
|
Zhang HB, Wang XD, Xu K, Li XG. The progress of prophylactic treatment in retinopathy of prematurity. Int J Ophthalmol 2018; 11:858-873. [PMID: 29862189 DOI: 10.18240/ijo.2018.05.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/28/2017] [Indexed: 12/19/2022] Open
Abstract
Retinopathy of prematurity (ROP) is a retinal vascular disorder frequently found in premature infants. Different therapeutic strategies have been developed to treat ROP. However, there are still many children with ROP suffering by severe limitations in vision or even blindness. Recently, ROP has been suggested to be caused by abnormal development of the retinal vasculature, but not simply resulted by retinal neovascularization which takes about 4 to 6wk after birth in premature infants. Thus, instead of focusing on how to reduce retinal neovascularization, understanding the pathological changes and mechanisms that occur prior to retinal neovascularization is meaningful, which may lead to identify novel target(s) for the development of novel strategy to promote the healthy growth of retinal blood vessels rather than passively waiting for the appearance of retinal neovascularization and removing it by force. In this review, we discussed recent studies about, 1) the pathogenesis prior to retinal neovascularization in oxygen-induced retinopathy (OIR; a ROP in animal model) and in premature infants with ROP; 2) the preclinical and clinical research on preventive treatment of early OIR and ROP. We will not only highlight the importance of the mechanisms and signalling pathways in regulating early stage of ROP but also will provide guidance for actively exploring novel mechanisms and discovering novel treatments for early phase OIR and ROP prior to retinal neovascularization in the future.
Collapse
Affiliation(s)
- Hong-Bing Zhang
- Eye Institute of Shaanxi Province; Xi'an First Hospital, Xi'an 710002, Shaanxi Province, China
| | - Xiao-Dong Wang
- Eye Institute of Shaanxi Province; Xi'an First Hospital, Xi'an 710002, Shaanxi Province, China
| | - Kun Xu
- Eye Institute of Shaanxi Province; Xi'an First Hospital, Xi'an 710002, Shaanxi Province, China
| | - Xiao-Gang Li
- Department of Internal Medicine; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| |
Collapse
|
|
43
|
Shulman JP, Hartnett ME. Pharmacotherapy and ROP: Going Back to the Basics. Asia Pac J Ophthalmol (Phila) 2018; 7:130-135. [PMID: 29701429 DOI: 10.22608/apo.201853] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Retinopathy of prematurity (ROP) is a leading cause of blindness in preterm infants around the world. Through the development of animal models and clinical trials our understanding of the pathophysiology of this disease and approach to therapy has evolved significantly since ROP was first described in the 1940s in the United States. The mainstay of treatment in ROP remains ablative laser therapy to the avascular retina but pharmacologic agents are being more and more commonly used with new targets for pharmacotherapy emerging. This paper summarizes our current understanding of the pathophysiology of ROP based on the data gleaned from animal models and discusses current approaches to pharmacotherapy.
Collapse
|
|
44
|
Garg J, Feng YX, Jansen SR, Friedrich J, Lezoualc'h F, Schmidt M, Wieland T. Catecholamines facilitate VEGF-dependent angiogenesis via β2-adrenoceptor-induced Epac1 and PKA activation. Oncotarget 2018; 8:44732-44748. [PMID: 28512254 PMCID: PMC5546514 DOI: 10.18632/oncotarget.17267] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 03/30/2017] [Indexed: 01/16/2023] Open
Abstract
Chronic stress has been associated with the progression of cancer and antagonists for β-adrenoceptors (βAR) are regarded as therapeutic option. As they are also used to treat hemangiomas as well as retinopathy of prematurity, a role of endothelial β2AR in angiogenesis can be envisioned. We therefore investigated the role of β2AR-induced cAMP formation by analyzing the role of the cAMP effector molecules exchange factor directly activated by cAMP 1 (Epac1) and protein kinase A (PKA) in endothelial cells (EC). Epac1-deficient mice showed a reduced amount of pre-retinal neovascularizations in the model of oxygen-induced retinopathy, which is predominantly driven by vascular endothelial growth factor (VEGF). siRNA-mediated knockdown of Epac1 in human umbilical vein EC (HUVEC) decreased angiogenic sprouting by lowering the expression of the endothelial VEGF-receptor-2 (VEGFR-2). Conversely, Epac1 activation by β2AR stimulation or the Epac-selective activator cAMP analog 8-p-CPT-2’-O-Me-cAMP (8-pCPT) increased VEGFR-2 levels and VEGF-dependent sprouting. Similar to Epac1 knockdown, depletion of the monomeric GTPase Rac1 decreased VEGFR-2 expression. As Epac1 stimulation induces Rac1 activation, Epac1 might regulate VEGFR-2 expression through Rac1. In addition, we found that PKA was also involved in the regulation of angiogenesis in EC since the adenylyl cyclase (AC) activator forskolin (Fsk), but not 8-pCPT, increased sprouting in Epac1-depleted HUVEC and this increase was sensitive to a selective synthetic peptide PKA inhibitor. In accordance, β2AR- and AC-activation, but not Epac1 stimulation increased VEGF secretion in HUVEC. Our data indicate that high levels of catecholamines, which occur during chronic stress, prime the endothelium for angiogenesis through a β2AR-mediated increase in endothelial VEGFR-2 expression and VEGF secretion.
Collapse
Affiliation(s)
- Jaspal Garg
- Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yu-Xi Feng
- Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sepp R Jansen
- Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Julian Friedrich
- 5th Medical Clinic, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
| | - Frank Lezoualc'h
- Institute of Cardiovascular and Metabolic Diseases, Inserm UMR-1048, Université Toulouse -Paul Sabatier, Toulouse, France
| | - Martina Schmidt
- Department of Molecular Pharmacology, Center of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Thomas Wieland
- Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| |
Collapse
|
|
45
|
Kaempfen S, Neumann RP, Jost K, Schulzke SM, Cochrane Neonatal Group. Beta-blockers for prevention and treatment of retinopathy of prematurity in preterm infants. Cochrane Database Syst Rev 2018; 3:CD011893. [PMID: 29499081 PMCID: PMC6494413 DOI: 10.1002/14651858.cd011893.pub2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Retinopathy of prematurity (ROP) is a vision-threatening disease of preterm neonates. The use of beta-adrenergic blocking agents (beta-blockers), which modulate the vasoproliferative retinal process, may reduce the progression of ROP or even reverse established ROP. OBJECTIVES To determine the effect of beta-blockers on short-term structural outcomes, long-term functional outcomes, and the need for additional treatment, when used either as prophylaxis in preterm infants without ROP, stage 1 ROP (zone I), or stage 2 ROP (zone II) without plus disease or as treatment in preterm infants with at least prethreshold ROP. SEARCH METHODS We searched the Cochrane Neonatal Review Group Specialized Register; CENTRAL (in the Cochrane Library Issue 7, 2017); Embase (January 1974 to 7 August 2017); PubMed (January 1966 to 7 August 2017); and CINAHL (January 1982 to 7 August 2017). We checked references and cross-references and handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings. SELECTION CRITERIA We considered for inclusion randomised or quasi-randomised clinical trials that used beta-blockers for prevention or treatment of ROP in preterm neonates of less than 37 weeks' gestational age. DATA COLLECTION AND ANALYSIS We used the standard methods of Cochrane and the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS We included three randomised trials (N = 366) in this review. Two of these studies were at high risk of bias. All studies reported on prevention of ROP and compared oral propranolol with placebo or no treatment. We found no trials assessing beta-blockers in infants with established stage 2 or higher ROP with plus disease.In one trial, study medication was started after one week of life, i.e. prior to the first ROP screening. The other two trials included preterm infants if they had stage 2 or lower ROP without plus disease. Based on the GRADE assessment, we considered evidence to be of low quality for the following outcomes: rescue treatment with anti-VEGF or laser therapy; and arterial hypotension or bradycardia requiring inotropic support. Evidence was of moderate quality for the following outcomes: progression to stage 2 with plus disease; progression to stage 3 ROP; and progression to stage 4 or 5 ROP.Meta-analysis of three trials (N = 366) suggested beneficial effects of oral beta-blockers on the risk of requiring anti-VEGF agents (typical risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.86; I² = 0%; typical risk difference (RD) -0.06, 95% CI -0.10 to -0.01; I² = 75%; number needed to treat for an additional beneficial outcome (NNTB) 18, 95% CI 14 to 84) and laser therapy (typical RR 0.54, 95% CI 0.32 to 0.89; typical RD -0.09, 95% CI -0.16 to -0.02; I² = 31%; NNTB 12, 95% CI 8 to 47). Meta-analysis of two trials (N = 161) demonstrated a beneficial effect of oral beta-blockers on progression to stage 3 ROP (typical RR 0.60, 95% CI 0.37 to 0.96; I² = 0%; typical RD -0.15, 95% CI -0.28 to -0.02; I² = 73%; NNTB 7, 95% CI 5 to 67). There was no significant effect of oral beta-blockers on progression to stage 2 ROP with plus disease or to stage 4 or 5 ROP. Although meta-analysis did not indicate a significant effect of beta-blockers on arterial hypotension or bradycardia, propranolol dosage in one study was reduced by 50% in infants of less than 26 weeks' gestational age due to severe hypotension, bradycardia, and apnoea in several participants. Analyses did not indicate significant effects of beta-blockers on complications of prematurity or mortality. None of the trials reported on long-term visual impairment. AUTHORS' CONCLUSIONS Limited evidence of low-to-moderate quality suggests that prophylactic administration of oral beta-blockers might reduce progression towards stage 3 ROP and decrease the need for anti-VEGF agents or laser therapy. The clinical relevance of those findings is unclear as no data on long-term visual impairment were reported. Adverse events attributed to oral propranolol at a dose of 2 mg/kg/d raise concerns regarding systemic administration of this drug for prevention of ROP at the given dose. There is insufficient evidence to determine the efficacy and safety of beta-blockers for prevention of ROP due to high risk of bias in two included trials and the lack of long-term functional outcomes. We would encourage researchers to conduct large, well-designed trials to confirm or refute the role of beta-blockers for prevention and treatment of ROP in preterm infants. Trials should report on long-term visual impairment. Researchers should consider dose-finding studies of systemic beta-blockers and topical administration of beta-blockers, in order to optimise drug delivery and minimise adverse events.
Collapse
Affiliation(s)
- Siree Kaempfen
- University of Basel Children's Hospital (UKBB)Department of NeonatologyBaselBaselSwitzerlandCH‐4031
| | - Roland P Neumann
- University of Basel Children's Hospital (UKBB)Department of NeonatologyBaselBaselSwitzerlandCH‐4031
| | - Kerstin Jost
- University of Basel Children's Hospital (UKBB)Department of NeonatologyBaselBaselSwitzerlandCH‐4031
| | - Sven M Schulzke
- University of Basel Children's Hospital (UKBB)Department of NeonatologyBaselBaselSwitzerlandCH‐4031
| | | |
Collapse
|
|
46
|
Cammalleri M, Locri F, Catalani E, Filippi L, Cervia D, Dal Monte M, Bagnoli P. The Beta Adrenergic Receptor Blocker Propranolol Counteracts Retinal Dysfunction in a Mouse Model of Oxygen Induced Retinopathy: Restoring the Balance between Apoptosis and Autophagy. Front Cell Neurosci 2017; 11:395. [PMID: 29375312 PMCID: PMC5770647 DOI: 10.3389/fncel.2017.00395] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 11/28/2017] [Indexed: 12/29/2022] Open
Abstract
In a mouse model of oxygen induced retinopathy (OIR), beta adrenergic receptor (BAR) blockade has been shown to recover hypoxia-associated retinal damages. Although the adrenergic signaling is an important regulator of apoptotic and autophagic processes, the role of BARs in retinal cell death remains to be elucidated. The present study was aimed at investigating whether ameliorative effects of BAR blockers may occur through their coordinated action on apoptosis and autophagy. To this aim, retinas from control and OIR mice untreated or treated with propranolol, a non-selective BAR1/2 blocker, were characterized in terms of expression and localization of apoptosis and autophagy markers. The effects of propranolol on autophagy signaling were also evaluated and specific autophagy modulators were used to get functional information on the autophagic effects of BAR antagonism. Finally, propranolol effects on neurodegenerative processes were associated to an electrophysiological investigation of retinal function by recording electroretinogram (ERG). We found that retinas of OIR mice are characterized by increased apoptosis and decreased autophagy, while propranolol reduces apoptosis and stimulates autophagy. In particular, propranolol triggers autophagosome formation in bipolar, amacrine and ganglion cells that are committed to die by apoptosis in response to hypoxia. Also our data argue that propranolol, through the inhibition of the Akt-mammalian target of rapamycin pathway, activates autophagy which decreases retinal cell death. At the functional level, propranolol recovers dysfunctional ERG by recovering the amplitude of a- and b-waves, and oscillatory potentials, thus indicating an efficient restoring of retinal transduction. Overall, our results demonstrate that BAR1/2 are key regulators of retinal apoptosis/autophagy, and that BAR1/2 blockade leads to autophagy-mediated neuroprotection. Reinstating the balance between apoptotic and autophagic machines may therefore be viewed as a future goal in the treatment of retinopathies.
Collapse
Affiliation(s)
| | - Filippo Locri
- Department of Biology, University of Pisa, Pisa, Italy
| | - Elisabetta Catalani
- Department for Innovation in Biological, Agro-Food and Forest Systems, University of Tuscia, Viterbo, Italy
| | - Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, Meyer University Children's Hospital, Florence, Italy
| | - Davide Cervia
- Department for Innovation in Biological, Agro-Food and Forest Systems, University of Tuscia, Viterbo, Italy
| | | | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy
| |
Collapse
|
|
47
|
Korkmaz L, Karaca C, Akin MA, Bastug O, Sahiner M, Ozdemir A, Gunes T, Ozturk MA, Kurtoglu S. Short-term Refractive Effects of Propranolol Hydrochloride Prophylaxis on Retinopathy of Prematurity in Very Preterm Newborns. Curr Eye Res 2017; 43:213-217. [PMID: 29135357 DOI: 10.1080/02713683.2017.1390769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE Retinopathy of prematurity (ROP) is one of the major problems of surviving premature infants with several ophthalmic morbidities such as increased risk of refractive errors, strabismus, and cortical visual impairment. Use of propranolol hydrochloride (PH) for the prevention of ROP is a new promising treatment modality. However, long-term effects are still to be defined. In our study, we aimed to investigate the short-term refractive effects of PH used for ROP prophylaxis in very preterm newborns. METHODS This is a prospective, randomized, double-blind, placebo-controlled study. Very preterm newborns with a birthweight less than or equal to 1500 g and/or born prior to 32 gestational weeks were included in the study. The subjects were randomly divided into two groups: control group (CG, n = 37) given placebo and PH group (PHG, n = 34) given PH starting from 4 weeks after birth (27.1 ± 2.1 day). PHG patients received PH therapy for about 1 month (25.7 ± 7.8 day). Anthropometric measurements including weight, length, and head circumference were recorded before PH treatment (at birth) and during eye control (at corrected age). Cycloplegic refraction values were measured by retinoscopy at corrected age (CG: 10.3 ± 4.3 months, PHG: 11.4 ± 4.8 months). RESULTS Anthropometric measurements including gestational age, weight, length, and head circumference were similar at birth and corrected age in both groups. The mean level of spherical refraction was significantly less hyperopic in the PHG than in the CG (CG: 1.37 ± 1.40 D, PHG: 0.37 ± 1.44 D) (p = 0.005). CONCLUSION PH may lead to myopic shift by affecting the beta-adrenergic receptors in the choroid or ciliary body of the developing eye. Long-term refractive follow-up is required in order to elucidate the effects of PH on emmetropization process of these very preterm infants.
Collapse
Affiliation(s)
- Levent Korkmaz
- a Division of Neonatology , Erciyes University Medical Faculty , Kayseri , Turkey
| | - Cagatay Karaca
- b Department of Ophthalmology , Erciyes University Medical Faculty , Kayseri , Turkey
| | - Mustafa Ali Akin
- c Division of Neonatology , Kayseri Training and Research Hospital , Kayseri , Turkey
| | - Osman Bastug
- a Division of Neonatology , Erciyes University Medical Faculty , Kayseri , Turkey
| | - Mustafa Sahiner
- b Department of Ophthalmology , Erciyes University Medical Faculty , Kayseri , Turkey
| | - Ahmet Ozdemir
- a Division of Neonatology , Erciyes University Medical Faculty , Kayseri , Turkey
| | - Tamer Gunes
- a Division of Neonatology , Erciyes University Medical Faculty , Kayseri , Turkey
| | - Mehmet Adnan Ozturk
- a Division of Neonatology , Erciyes University Medical Faculty , Kayseri , Turkey
| | - Selim Kurtoglu
- a Division of Neonatology , Erciyes University Medical Faculty , Kayseri , Turkey
| |
Collapse
|
|
48
|
Retinal vasculature development in health and disease. Prog Retin Eye Res 2017; 63:1-19. [PMID: 29129724 DOI: 10.1016/j.preteyeres.2017.11.001] [Citation(s) in RCA: 218] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 11/02/2017] [Accepted: 11/06/2017] [Indexed: 12/17/2022]
Abstract
Development of the retinal vasculature is based on highly coordinated signalling between different cell types of the retina, integrating internal metabolic requirements with external influences such as the supply of oxygen and nutrients. The developing mouse retinal vasculature is a useful model system to study these interactions because it is experimentally accessible for intra ocular injections and genetic manipulations, can be easily imaged and develops in a similar fashion to that of humans. Research using this model has provided insights about general principles of angiogenesis as well as pathologies that affect the developing retinal vasculature. In this review, we discuss recent advances in our understanding of the molecular and cellular mechanisms that govern the interactions between neurons, glial and vascular cells in the developing retina. This includes a review of mechanisms that shape the retinal vasculature, such as sprouting angiogenesis, vascular network remodelling and vessel maturation. We also explore how the disruption of these processes in mice can lead to pathology - such as oxygen induced retinopathy - and how this translates to human retinopathy of prematurity.
Collapse
|
|
49
|
Chan-Ling T, Gole GA, Quinn GE, Adamson SJ, Darlow BA. Pathophysiology, screening and treatment of ROP: A multi-disciplinary perspective. Prog Retin Eye Res 2017; 62:77-119. [PMID: 28958885 DOI: 10.1016/j.preteyeres.2017.09.002] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 09/18/2017] [Accepted: 09/20/2017] [Indexed: 12/24/2022]
Abstract
The population of infants at risk for retinopathy of prematurity (ROP) varies by world region; in countries with well developed neonatal intensive care services, the highest risk infants are those born at less than 28 weeks gestational age (GA) and less than 1 kg at birth, while, in regions where many aspects of neonatal intensive and ophthalmological care are not routinely available, more mature infants up to 2000 g at birth and 37 weeks GA are also at risk for severe ROP. Treatment options for both groups of patients include standard retinal laser photocoagulation or, more recently, intravitreal anti-VEGF drugs. In addition to detection and treatment of ROP, this review highlights new opportunities created by telemedicine, where screening and diagnosis of ROP in remote locations can be undertaken by non-ophthalmologists using digital fundus cameras. The ophthalmological care of the ROP infant is undertaken in the wider context of neonatal care and general wellbeing of the infant. Because of this context, this review takes a multi-disciplinary perspective with contributions from retinal vascular biologists, pediatric ophthalmologists, an epidemiologist and a neonatologist. This review highlights the latest insights regarding cellular and molecular mechanisms in the formation of the retinal vasculature in the human infant, pathogenesis of ROP, detection and treatment of severe ROP, the risks and benefits of anti-VEGF therapy, the identification of new therapies over the horizon, and the optimal neonatal care regimen for best ROP outcomes, and the benefits and pitfalls of telemedicine in the remote screening and diagnosis of ROP, all of which have the potential to improve ROP outcomes.
Collapse
Affiliation(s)
- Tailoi Chan-Ling
- Department of Anatomy, School of Medical Sciences and Bosch Institute, University of Sydney, NSW 2006, Australia.
| | - Glen A Gole
- Discipline of Paediatrics and Child Health, University of Queensland, Qld Children's Hospital, Sth Brisbane, Qld 4101, Australia.
| | - Graham E Quinn
- Division of Ophthalmology, The Children's Hospital of Philadelphia and Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Samuel J Adamson
- Department of Anatomy, School of Medical Sciences and Bosch Institute, University of Sydney, NSW 2006, Australia
| | - Brian A Darlow
- Department of Paediatrics, University of Otago, Christchurch, New Zealand.
| |
Collapse
|
|
50
|
Filippi L, Cavallaro G, Berti E, Padrini L, Araimo G, Regiroli G, Bozzetti V, De Angelis C, Tagliabue P, Tomasini B, Buonocore G, Agosti M, Bossi A, Chirico G, Aversa S, Pasqualetti R, Fortunato P, Osnaghi S, Cavallotti B, Vanni M, Borsari G, Donati S, Nascimbeni G, la Marca G, Forni G, Milani S, Cortinovis I, Bagnoli P, Dal Monte M, Calvani AM, Pugi A, Villamor E, Donzelli G, Mosca F. Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial. BMC Pediatr 2017; 17:165. [PMID: 28709412 PMCID: PMC5513165 DOI: 10.1186/s12887-017-0923-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 07/05/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.
Collapse
Affiliation(s)
- Luca Filippi
- Neonatal Intensive Care Unit - Medical Surgical Fetal-Neonatal Department, Meyer University Children's' Hospital, viale Pieraccini 24, 50134, Florence, Italy.
| | - Giacomo Cavallaro
- Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Elettra Berti
- Neonatal Intensive Care Unit - Medical Surgical Fetal-Neonatal Department, Meyer University Children's' Hospital, viale Pieraccini 24, 50134, Florence, Italy
| | - Letizia Padrini
- Neonatal Intensive Care Unit - Medical Surgical Fetal-Neonatal Department, Meyer University Children's' Hospital, viale Pieraccini 24, 50134, Florence, Italy
| | - Gabriella Araimo
- Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Giulia Regiroli
- Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Valentina Bozzetti
- Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy
| | - Chiara De Angelis
- Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy
| | - Paolo Tagliabue
- Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy
| | - Barbara Tomasini
- Department of Pediatrics, Obstetrics and Reproductive Medicine, Neonatal Intensive Care Unit, University Hospital of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy
| | - Giuseppe Buonocore
- Department of Molecular and Developmental Medicine, University of Siena, Via Banchi di Sotto, 55, 53100, Siena, Italy
| | - Massimo Agosti
- Neonatal Intensive Care Unit, Del Ponte Hospital, Varese, Italy
| | - Angela Bossi
- Neonatal Intensive Care Unit, Del Ponte Hospital, Varese, Italy
| | - Gaetano Chirico
- Neonatal Intensive Care Unit, Children's Hospital, University Hospital "Spedali Civili" of Brescia, Brescia, Italy
| | - Salvatore Aversa
- Neonatal Intensive Care Unit, Children's Hospital, University Hospital "Spedali Civili" of Brescia, Brescia, Italy
| | - Roberta Pasqualetti
- Pediatric Ophthalmology, A. Meyer" University Children's Hospital, Florence, Italy
| | - Pina Fortunato
- Pediatric Ophthalmology, A. Meyer" University Children's Hospital, Florence, Italy
| | - Silvia Osnaghi
- Department of Ophthalmology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Barbara Cavallotti
- Department of Ophthalomolgy, ASST Monza, San Gerardo Hospital, Monza, Italy
| | - Maurizio Vanni
- Pediatric Ophthalmology, University Hospital of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy
| | - Giulia Borsari
- Pediatric Ophthalmology, University Hospital of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy
| | - Simone Donati
- Department of Surgical and Morphological Sciences, Section of Ophthalmology, University of Insubria, Varese, Italy
| | - Giuseppe Nascimbeni
- Department of Ophthalmology, University Hospital "Spedali Civili" of Brescia, Brescia, Italy
| | - Giancarlo la Marca
- Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Newborn Screening, Biochemistry and Pharmacology Laboratory, Meyer Children's University Hospital, Florence, Italy
| | - Giulia Forni
- Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Newborn Screening, Biochemistry and Pharmacology Laboratory, Meyer Children's University Hospital, Florence, Italy
| | - Silvano Milani
- Laboratory "G.A. Maccacro", Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Ivan Cortinovis
- Laboratory "G.A. Maccacro", Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Paola Bagnoli
- Department of Biology, Unit of General Physiology, University of Pisa, Pisa, Italy
| | - Massimo Dal Monte
- Department of Biology, Unit of General Physiology, University of Pisa, Pisa, Italy
| | - Anna Maria Calvani
- Department of Pharmacy, "A. Meyer" University Children's Hospital, Florence, Italy
| | - Alessandra Pugi
- Clinical Trial Office, "A. Meyer" University Children's Hospital, viale Pieraccini 24, 50134, Florence, Italy
| | - Eduardo Villamor
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, The Netherlands
| | - Gianpaolo Donzelli
- Neonatal Intensive Care Unit - Medical Surgical Fetal-Neonatal Department, Meyer University Children's' Hospital, viale Pieraccini 24, 50134, Florence, Italy
| | - Fabio Mosca
- Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| |
Collapse
|