Treating infants with 0.2% propranolol eye micro‐drops drastically reduced the progression of retinopathy of prematurity

Scaramuzzo, Rosa Teresa; Bagnoli, Paola; Dal Monte, Massimo; Cammalleri, Maurizio; Pini, Alessandro; Ballini, Sandy; Bendinelli, Anna; Desideri, Ielizza; Ciantelli, Massimiliano; Filippi, Luca

doi:10.1111/apa.16850

Cited by 4 publications

(2 citation statements)

References 5 publications

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“…A more recent study confirmed the efficacy of propranolol eye drops at a concentration of 0.2% without significant adverse effects ( 113 ). To reduce the percentage of the drug absorbed through the conjunctival and nasal vessels and to increase the safety profile of the study, the infants received micro-drops administered using a variable volume pipette ( Figure 1 ).…”

Section: Propranolol In Humans With Retinopathy Of Prematuritymentioning

confidence: 83%

Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression

Pascarella,

Scaramuzzo,

Pini

et al. 2024

Front. Pediatr.

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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.

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Section: Propranolol In Humans With Retinopathy Of Prematuritymentioning

confidence: 83%

Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression

Pascarella,

Scaramuzzo,

Pini

et al. 2024

Front. Pediatr.

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“…In order to improve the safety profile of propranolol treatment, eye drops have been tested in ROP infants on the basis of preclinical findings demonstrating that in the OIR model topical propranolol reaches the posterior part of the eye ( Dal Monte et al, 2013 ) in which propranolol concentration appears to be much higher than in the plasma as demonstrated in the rabbit eye ( Padrini et al, 2014 ). According to the efficacy of topical formulations of propranolol for IH ( Pahl and McLean, 2022 ), treating infants with propranolol eye micro-drops at a concentration of 0.2% has been shown to reduce ROP progression without side effects ( Filippi et al, 2019 ; Scaramuzzo et al, 2023 ), while propranolol concentration at 0.1% had no efficacy ( Filippi et al, 2017 ). However, clinical trials using eye drops with propranolol are strongly limited by the low number of preterm infants in the treated cohort and the lack of randomized controlled group to draw definitive conclusions, Although the promising results of the clinical trials might encourage the development of additional studies, determination of the clinical importance of propranolol therapy in ROP requires a more rational approach to the design of prospective clinical trials.…”

Section: Introductionmentioning

confidence: 99%

A promising case of preclinical-clinical translation: β-adrenoceptor blockade from the oxygen-induced retinopathy model to retinopathy of prematurity

Cammalleri,

Filippi,

Dal Monte

et al. 2024

Front. Physiol.

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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.

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Comparison of Different Doses of Oral and Ocular Propranolol for Retinopathy of Prematurity: A Network Meta-Analysis

Ortiz-Seller,

Martorell,

Roselló

et al. 2024

Pediatr Drugs

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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. ...

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Treating infants with 0.2% propranolol eye micro‐drops drastically reduced the progression of retinopathy of prematurity

Cited by 4 publications

References 5 publications

Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression

Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression

A promising case of preclinical-clinical translation: β-adrenoceptor blockade from the oxygen-induced retinopathy model to retinopathy of prematurity

Comparison of Different Doses of Oral and Ocular Propranolol for Retinopathy of Prematurity: A Network Meta-Analysis

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