Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity.
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ABSTRACT:
SUBMITTER: Beharry KD
PROVIDER: S-EPMC4808450 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
Publications
Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity.
Beharry Kay D KD Valencia Gloria B GB Lazzaro Douglas R DR Aranda Jacob V JV
Seminars in perinatology 20160129 3
Retinopathy of prematurity (ROP), a significant morbidity in prematurely born infants, is the most common cause of visual impairment and blindness in children and persists till adulthood. Strict control of oxygen therapy and prevention of intermittent hypoxia are the keys in the prevention of ROP, but pharmacologic interventions have decreased risk of ROP. Various drug classes such as methylxanthines (caffeine), VEGF inhibitors, antioxidants, and others have decreased ROP occurrence. The timing ...[more]
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Project description:More than 450,000 babies are born prematurely in the USA every year. The improved survival of even the most vulnerable low body weight preterm infants has, despite improving health outcomes, led to the resurgence in preterm complications including one of the major causes for blindness in children, retinopathy of prematurity (ROP). The current mainstay in ROP therapy is laser photocoagulation and the injection of vascular endothelial growth factor (VEGF) antibodies in the late stages of the disease after the onset of neovascularization. Both are proven options for ophthalmologists to treat the severe forms of late ROP. However, laser photocoagulation destroys major parts of the retina, and the injection of VEGF antibodies, although rather simple to administer, may cause a systemic suppression of normal vascularization, which has not been studied in sufficient depth. However, the use of neither VEGF antibody nor laser treatment prevents ROP, which should be the long-term goal. It should be possible to prevent ROP by more closely mimicking the intrauterine environment after preterm birth. Such preventive measures include preventing the toxic postbirth influences (eg, oxygen excess) as well as providing the missing intrauterine factors (eg, insulin growth factor 1) and are likely to also reduce other complications of premature birth as well as ROP. This review is meant to summarize the current knowledge on the prevention of ROP with a particular emphasize on the use of insulin growth factor 1 supplementation.
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Project description:To identify the prevention situation, the main factors influencing prevention effects and to develop control measures over retinopathy of prematurity in China.Using stratified random sampling method, we randomly selected 23 provincial and ministerial hospitals (8 in Guangdong province, 5 in Hunan province and 10 in Shaanxi province), 81 municipal hospitals (38 in Guangdong province, 19 in Hunan province and 24 in Shaanxi province), 180 district and county hospitals (76 in Guangdong province, 57 in Hunan province and 47 in Shaanxi province) in China. A total of 284 hospitals were enrolled in the study, with questionnaires distributed investigating the status and constrain factors of ROP presentation. Significant outcomes were analyzed thereafter by SPSS 19.0.The screening rate of ROP in medical institutions from eastern, central and western China were 84.6%, 35.0% and 56.7%, respectively. The screening rate of tertiary and secondary medical institutions were 84.6% and 25.7% in the eastern, 35.0% and 4.9% in the central, 56.7% and 5.9% in the western region. Screening was carried out better in the tertiary than that in the secondary and primary institutions. Treatment for ROP was available in 15.7% of all the tertiary hospitals surveyed. Lack of professionals, equipments and technologies were considered to be major restrain factors for screening.The ROP screening and treatment status have demonstrated significant regional diversity due to uneven distribution of medical resources in China. Developed areas had established intraregional cooperation models, whereas less-developed areas should consider set up a large-scale, three-level ROP prevention network. It is of paramount importance that education and training towards ophthalmologists should be vigorously strengthened. It is strongly recommended that implement ROP telemedicine and integrated ROP prevention and management platforms through the Internet should be established.
| S-EPMC5813392 | biostudies-literature
Project description:Retinopathy of prematurity (ROP) is the most common cause of childhood blindness worldwide and is caused by oxygen therapy necessary to prevent mortality after premature birth. We have previously demonstrated the efficacy of systemic hypoxia inducible factor (HIF) stabilization through HIF prolyl hydroxylase inhibition (HIF PHi) in protecting retinal vasculature from oxygen toxicity in a mouse model of ROP or oxygen induced retinopathy (OIR). We definitively demonstrated that hepatic HIF-1 can be activated to confer this protection using systemic dimethyloxalylglycine (DMOG) to prevent HIF-1α degradation. In this study we compare Roxadustat, a small molecule stabilizer of HIF-1 currently in phase 3 clinical trials for increasing erythropoiesis in adult patients with chronic kidney disease, to DMOG. We demonstrate that Roxadustat induces vascular protection during hyperoxia to induce the coordinated sequential growth of retinal vasculature with a 3-fold reduction in oxygen induced capillary loss (p-=0.001). In order to define the molecular mechanism of protection, we further compared the transcriptome of both liver and retina after systemic treatment with Roxadustat or DMOG. Similar gene expression profiles were identified in liver but very different effects on transcription were found in retinal tissues because Roxadustat, in contrast to DMOG, directly targets retina, confirmed by western blot and by rescue of the hepatic HIF-1 KO, two criteria that DMOG treatment is unable to fulfill. Systems pharmacologic analysis demonstrates that Roxadustat induces typical HIF regulated genes critical to aerobic glycolysis in liver and retinal tissues whereas DMOG, acting through either secreted hepatokines or by influence of systemic DMOG, downregulates cell adhesion/extracellular matrix interaction pathways while increasing expression of histone cluster genes. Stratification of liver transcriptomes to secreted gene products again shows close consensus of hepatic genes induced by both small molecules, and includes upregulation of a plethora of angiogenic proteins such as plasminogen activator inhibitor (PAI-1), erythropoietin (EPO), and orosomucosoid 2 (ORM2). Secondary validation of these transcripts by serum ELISA confirms secretion of EPO and PAI-1 into blood from liver. These findings definitively demonstrate that HIF stabilization can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect, hepatic HIF-1 stabilization and increased serum angiokines. Systems pharmacology analysis therefore explains why intermittent, low dosage of small molecule HIF stabilizers creates a profound protective phenotype, because both pathways can take advantage of cytoprotection induced by the liver and by retina synergistically. These data provide a rationale for considering low dose, intermittent systemic administration of Roxadustat, currently in phase 3 trials in adults with chronic kidney disease, to eradicate ROP in children.
2016-05-03 | GSE74170 | GEO
Project description:BackgroundMore than 11 000 children are examined for possible retinopathy of prematurity in Germany each year, and 2-5% of them are treated for it. Even though screening and treatment programs are in place, the affected children can still suffer visual impairment.MethodsIn this article, we summarize the pathogenesis, screening, and treatment of retinopathy of prematurity on the basis of a selective review of pertinent literature, retrieved by a PubMed search. The article centers on publications from 2011 to 2015 on the new option of treatment with VEGF inhibitors and discusses it in comparison to laser therapy.ResultsAll premature neonates with a low gestational age at birth, low birth weight, or prolonged exposure to supplemental oxygen must undergo screening by an ophthalmologist. Laser therapy is effective for stages 1-3 and for aggressive posterior retinopathy of prematurity. Its disadvantages are the induction of scarring and the development of severe myopia in 17-40% of the children so treated. Anti-VEGF treatment (VEGF = vascular endothelial growth factor) does not induce any visible scarring and seems to cause less myopia, but long-term data on safety, dosing, and the choice of anti-VEGF drug are still lacking.ConclusionThe available evidence for anti-VEGF treatment is on a much lower level than the evidence for laser therapy. Anti-VEGF may be a way to avoid the disadvantages of laser therapy (scarring and severe myopia). Unlike laser therapy, however, the intravitreal injection of VEGF inhibitors may suppress systemic VEGF levels and potentially harm the developing brain, lungs, or other organs. The currently open questions about anti-VEGF treatment concern its dosing, choice of drug, and long-term safety.
| S-EPMC4647313 | biostudies-literature
Project description:Introduction:Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide. Areas covered:Recent methods to identify and manage treatment-warranted vascularly active ROP are recognized and being compared to standard care by laser treatment in prospective large-scale clinical studies. Pharmacologic anti-angiogenic (anti-VEGF) treatment has changed the natural history of vascularly active ROP by reducing stage 3 intravitreal neovascularization and extending physiologic retinal vascularization in many infants. Tractional retinal detachments in stage 4 ROP after treatment with anti-VEGF agents show additional fibrovascular complexity compared to eyes treated with laser only. We review current management and outcomes for vascularly active and fibrovascular retinal detachment in ROP (stages 3, 4, 5 ROP), highlighting the evidence from recent clinical studies. Included are technical details important in surgery for retinal detachment in ROP. Literature searches were employed through PubMed. Expert opinion:Methods in pediatric imaging, safer pharmacologic treatments, and surgical techniques continue to advance to improve future ROP outcomes.
| S-EPMC6874220 | biostudies-literature
Project description: Not available
| S-EPMC4020289 | biostudies-literature
Project description:The immature retinas of preterm neonates are susceptible to insults that disrupt neurovascular growth, leading to retinopathy of prematurity. Suppression of growth factors due to hyperoxia and loss of the maternal-fetal interaction result in an arrest of retinal vascularisation (phase 1). Subsequently, the increasingly metabolically active, yet poorly vascularised, retina becomes hypoxic, stimulating growth factor-induced vasoproliferation (phase 2), which can cause retinal detachment. In very premature infants, controlled oxygen administration reduces but does not eliminate retinopathy of prematurity. Identification and control of factors that contribute to development of retinopathy of prematurity is essential to prevent progression to severe sight-threatening disease and to limit comorbidities with which the disease shares modifiable risk factors. Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids, as well as curbing of the effects of infection and inflammation to promote normal growth and limit suppression of neurovascular development.
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Project description:Background/objectivesFluorescein angiography (FA) has been a pivotal tool to study the pathophysiology of retinopathy of prematurity (ROP) in vivo. We examined the course of ROP using FA in order to assess the predictive value of angiographic features.Subjects/methodsThis is an observational retrospective cohort multi-center study of eyes screened for ROP with binocular indirect ophthalmoscope and with FA. All infants undergoing screening examination for ROP who had retinal vasculature limited to Zone I and posterior Zone II vascularization underwent FA between 31 and 34 weeks postmenstrual age. RetCam fundus imaging and video digital fluorescein angiography were performed in the neonatal intensive care units. Masked grading of the FA images was retrospectively conducted by two ROP expert ophthalmologists. Ten criteria that describe retinovascular and choroidal features on FA were used to assess their predictive value for development of treatment-requiring ROP.ResultsA total of 98 eyes of 56 patients were included for this study. FAs of eyes of premature infants show a wide range of features either at the junction between the vascular and avascular retina and posteriorly to that. Among the angiographic features evaluated, leakage, shunts and hyperfluorescent lesions at the junction between vascular and avascular zone were predictive of the development of treatment-requiring ROP (p < 0.05), but findings in the posterior vascularized retina were not.ConclusionsFA can add to our understanding of the evolution of vascular abnormalities in the course of ROP and can help predict which eyes will go on to treatment.
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Project description:PURPOSE OF REVIEW:Currently, severe retinopathy of prematurity (ROP) is diagnosed by clinical evaluation and not a laboratory test. Laser is still considered standard care. However, anti-vascular endothelial growth factor (VEGF) agents are being used and there are questions whether and/or if to use them, what dose or type of agent should be considered and what agent may be most beneficial in specific cases. Also unclear are the effects of laser or anti-VEGF on severe ROP, refractive outcomes or infant development. This article reviews recent studies related to these questions and other trials for severe ROP. RECENT FINDINGS:Imaging studies identify biomarkers of risk (plus disease, stage 3 ROP, and ROP in zone I). Intravitreal bevacizumab or ranibizumab are reported effective in treating aggressive posterior ROP in small series. Recurrences and effects on myopia vary among studies. Use of anti-VEGF agents affects cytokines in the infant blood and reduces systemic VEGF for up to 2 months, raising potential safety concerns. The effects of treatment vary based on infant size and are not comparable. Evidence for most studies is not high. SUMMARY:Studies support experimental evidence that inhibiting VEGF reduces stage 3 ROP and peripheral avascular retina. Ongoing large-scale clinical trials may provide clarity for best treatments of severe ROP. Current guidelines hold for screening and treatment for type 1 ROP.
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