Toxicity and in vivo release profile of sirolimus from implants into the vitreous of rabbits’ eyes

Paiva, Mayara Rodrigues Brandão de; Lage, Nayara Almeida; Guerra, Maria Carolina Andrade; Mol, Marcos Paulo Gomes; Ribeiro, Marcela Coelho Silva; Fulgêncio, Gustavo de Oliveira; Gomes, Dawidson Assis; César, Isabela Costa; Fialho, Sílvia Ligório; Silva-Cunha, Armando

doi:10.1007/s10633-018-9664-8

Cited by 13 publications

(4 citation statements)

References 56 publications

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“…These may suggest a potential mechanism to improve impaired visual signaling in the retina. This amplitude augmenting effect has been previously reported at least once to our knowledge by De Paivaet al (2019), with the use of sustained-release rapamycin systems and was considered transient and clinically irrelevant (52). Also, a protective effect of rapamycin on visual impairment during inflammation has been reported as the attenuation in a-and b-wave reduction due to induced inflammation (53).…”

Section: Electroretinographymentioning

confidence: 51%

Toxicity Evaluation of a Novel Rapamycin Liposomal Formulation After Subconjunctival and Intravitreal Injection

García-Santisteban¹,

Bernad‐Bernad²,

Ambrosio³

et al. 2020

Preprint

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Purpose: Safety and toxicity evaluation of a nove liposome-encapsulated rapamycin formulation, intended for autoimmune ocular disorders. Methods: The formulation (60 and 180 μg for subconjunctival and 40 and 440 μg for intravitreal administration) were assessed through micronucleus polychromatic erythrocytes production, and irritability by HET CAM and pyrogenicity testing.Subconjunctival and intravitreal administration of the formulation were performed to evaluate subacute and acute toxicity, respectively. Shapiro Wilk and Kolmogorov-Smirnov tests were applied for normality. Pearson and Spearman Correlation tests for variable comparison. Differences between groups in biochemical and hematological parameters were evaluated by ANOVA test with significance determination by t-Holm-Sidak post-hoc test. A t-test was employed to compare independent, normally distributed variables. Numeric score was assigned to histopathological classification. Data was analyzed by a one way no parametric Kruskal-Wallis and the Mann-Whitney tests. Significance was considered when p<0.05 Results: No significant toxicity directly related to the preparation was detected. Micronucleus count, mucous irritation score, and pyrogenicity were negative. Pathology demonstrated no damage related to the formulation after subconjunctival injection. After intravitreal injection, only lens injury associated with the technique was observed. Retinal function was also conserved in electroretinography. (ERG). Conclusions: The preparation evaluated offers a good toxicity and safety profile when injected in a subconjunctival or intravitreal manner in an animal model. A clinical trial conducted in humans is highly warranted, as it could reveal an alternative immunosuppressive treatment for ophthalmological immune-mediated pathologies.

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Section: Electroretinographymentioning

confidence: 51%

Toxicity Evaluation of a Novel Rapamycin Liposomal Formulation After Subconjunctival and Intravitreal Injection

García-Santisteban¹,

Bernad‐Bernad²,

Ambrosio³

et al. 2020

Preprint

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“…PLGA sirolimus implants showed decreased inflammatory scores and significant reduction of proteins even after 35 days in treated eyes with no toxic effects in rabbit eyes. 88,90 Abud et al 91 evaluated the in vivo and in vitro toxicity (rabbit eyes) of liposomal-encapsulated sirolimus (LES) and found them to be stable even after 3 months. ARPE-19 cell viability and terminal deoxynucleotidyl transferase nick-end labelling (TUNEL) assay were comparable between LES, empty liposomes, and balanced salt solution (BSS) groups, and glial fibrillary acid protein (GFAP) immunohistochemistry did not show activation of Müller cells.…”

Section: Sirolimusmentioning

confidence: 99%

A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology

et al. 2022

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Systemic immunosuppressants and biologicals have been a valuable tool in the treatment of inflammatory diseases and malignancies. The safety profile of these drugs has been debatable, especially in localized systems, such as the eye. This has led to the search for fairly local approaches, such as intravitreal, subconjunctival, and topical route of administration. Immunosuppressants have been used as a second-line drug in patients intolerable to corticosteroids or those who develop multiple recurrences on weaning corticosteroids. Similarly, biologicals have also been used as the next line of therapy, when adequate control of inflammation could not be attained or immunosuppressants were contraindicated to patients. Intravitreal immunosuppressants, such as methotrexate and sirolimus, have been extensively studied in noninfectious posterior uveitis, whereas limited studies have established the efficacy of intravitreal biologicals, such as infliximab and adalimumab. Most of these drugs have shown good safety profile and tolerability in animal studies alone and have not been studied further in human subjects. However, most of the studies in literature are single-case reports or case series which limits the level of evidence. In this comprehensive review, we discuss the mechanism of action, pharmacodynamics, pharmacokinetics, indications, efficacy, and side effects of different intravitreal immunosuppressants and biologicals that have been studied in literature.

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“…Although characterized by anti-inflammatory activity which makes the sirolimus as alternative treatment for recalcitrant NIU with or without macular oedema, its short half-life requiring multiple reinjections is one of its main disadvantages. To date, the safety of a biodegradable intravitreal sirolimus implant has been tested in rabbits with promising results [49].…”

Section: Sirolimusmentioning

confidence: 99%

Intraocular therapy in noninfectious uveitis

Modugno

Testi

Pavésio

2021

J Ophthal Inflamm Infect

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Systemic corticosteroids and immunosuppressant agents are the mainstay of therapy for non-infectious uveitis (NIU). However, the risks associated with systemic administration and the need of delivering an effective and safe anti-inflammatory treatment targeted to the site of inflammation have prompt the use of local therapy in the management of NIU. This review will analyse the different local treatment options available, including corticosteroids, anti-vascular endothelial growth factor (VEGF), methotrexate and the recent biologics.

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Toxicity and in vivo release profile of sirolimus from implants into the vitreous of rabbits’ eyes

Cited by 13 publications

References 56 publications

Toxicity Evaluation of a Novel Rapamycin Liposomal Formulation After Subconjunctival and Intravitreal Injection

Toxicity Evaluation of a Novel Rapamycin Liposomal Formulation After Subconjunctival and Intravitreal Injection

A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology

Intraocular therapy in noninfectious uveitis

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