Ocular toxicity and distribution of subconjunctival and intravitreal rapamycin in horses.
Abstract: In vitro photosensitivity of rapamycin (RAPA) and ocular toxicity and distribution of intravitreal and subconjunctival RAPA was evaluated in normal horses. RAPA (2.5 mg, 5 mg, and 10 mg) was placed in 10 mL of PBS and maintained in a water bath at 37 degrees C, kept in the dark or subjected to room light, and sampled for up to 3 months for RAPA levels. Six normal adult horses received either 5 mg (n = 2) or 10 mg (n = 2) of RAPA intravitreally or 10 mg (n = 2) subconjunctivally. Ophthalmic exams and electroretinography (ERG) were performed prior to injection and on days 1, 7, 14, and 21 post-injection. Eyes were enucleated and samples were collected for RAPA concentrations and histopathology. No difference in light vs. dark RAPA concentrations was observed, suggesting a lack of RAPA phototoxicity. No evidence of ocular toxicity was noted on ophthalmic examination or histopathology. RAPA was not detected intraocularly 7 days post-injection in eyes receiving subconjunctival RAPA, but was detected in the vitreous at 21 days post-injection. Drug could be detected in both the aqueous and vitreous humor after intravitreal injection. Further study is needed to determine the efficacy of intravitreal RAPA.
Publication Date: 2008-11-13 PubMed ID: 19000272DOI: 10.1111/j.1365-2885.2008.00986.xGoogle Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research article explores the potential for eye damage (ocular toxicity) and distribution in horses from two types of injections of a drug called rapamycin (RAPA). The researchers found no obvious signs of toxicity or damaging effects on the eye and the drug could be traced in the eye for up to 21 days after an intravitreal (inside the eye) injection.
Introduction and Methodology
- Researchers tested the effects of rapamycin (RAPA), a medication with anti-inflammatory and immunosuppressive properties, on the eyes of horses. The goal was to explore photo-toxicity (the potential of the drug to cause harm when exposed to light), ocular toxicity, and drug distribution.
- Different dosages of the drug (2.5mg, 5mg, 10mg) were mixed in 10ml of PBS (a balanced salt solution), maintained at 37 degrees Celsius, and kept either in darkness or exposed to room light. Sampling for RAPA was performed over a 3 month period.
- The researchers used six healthy adult horses that either received 5mg, 10mg of RAPA intravitreally (injected into the vitreous humor of the eye) or 10mg subconjunctivally (injected under the conjunctiva of the eye).
- Procedures such as ophthalmic exams, electroretinography (ERG), and histopathology were performed to monitor any potential changes in the eyes of the horses. These procedures were carried out before the injection and on days 1, 7, 14, and 21 after the injection.
Findings
- The researchers discovered no significant difference between RAPA concentrations kept in light as compared to those kept in darkness. This suggests that RAPA does not have phototoxic properties.
- Throughout the examination period, no signs of ocular toxicity were observed in the horses, either through ophthalmological examinations or histopathology.
- RAPA was undetectable intraocularly (within the eye) 7 days post-injection in eyes that received the drug subconjunctivally. But, it was identified in the vitreous humor 21 days post-injection. The drug was found in both the aqueous humor (the watery substance in the front part of the eye) and the vitreous humor (the gel-like substance in the back part of the eye) after intravitreal injection.
Conclusions and Future Work
- The researchers concluded that the tested drugs revealed no significant adverse effects on the eyes of the horses. However, they suggested that further investigation is needed to determine the effectiveness of RAPA when applied intravitreally, as distribution varied depending on the method of administration.
Cite This Article
APA
Douglas LC, Yi NY, Davis JL, Salmon JH, Gilger BC.
(2008).
Ocular toxicity and distribution of subconjunctival and intravitreal rapamycin in horses.
J Vet Pharmacol Ther, 31(6), 511-516.
https://doi.org/10.1111/j.1365-2885.2008.00986.x Publication
Researcher Affiliations
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA.
MeSH Terms
- Animals
- Anti-Bacterial Agents / adverse effects
- Anti-Bacterial Agents / pharmacokinetics
- Anti-Bacterial Agents / therapeutic use
- Chromatography, High Pressure Liquid
- Dermatitis, Phototoxic
- Horses
- Sirolimus / adverse effects
- Sirolimus / pharmacokinetics
- Sirolimus / therapeutic use
- Tissue Distribution
- Uveitis / drug therapy
- Uveitis / veterinary
Citations
This article has been cited 10 times.- Salcedo-Ledesma A, Córdoba A, Zatarain-Barrón NC, Graue-Hernández EO, Garfias Y, Morales Flores N, García-Sánchez GA, García-Santisteban D, Linares-Alba MA, García-Santisteban R, Navas A. Subconjunctival Sirolimus-Loaded Liposomes for the Treatment of Moderate-to-Severe Dry Eye Disease. Clin Ophthalmol 2023;17:1295-1305.
- Hasan N, Chawla R, Shaikh N, Kandasamy S, Azad SV, Sundar MD. A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology. Ther Adv Ophthalmol 2022 Jan-Dec;14:25158414221097418.
- Li H, Zhang Z, Li Y, Su L, Duan Y, Zhang H, An J, Ni T, Li X, Zhang X. Therapeutic Effect of Rapamycin-Loaded Small Extracellular Vesicles Derived from Mesenchymal Stem Cells on Experimental Autoimmune Uveitis. Front Immunol 2022;13:864956.
- Fischer BM, McMullen RJ Jr, Reese S, Brehm W. Intravitreal injection of low-dose gentamicin for the treatment of recurrent or persistent uveitis in horses: Preliminary results. BMC Vet Res 2019 Jan 16;15(1):29.
- De Paiva MRB, Lage NA, Guerra MCA, Mol MPG, Ribeiro MCS, Fulgêncio GO, Gomes DA, Da Costa César I, Fialho SL, Silva-Cunha A. Toxicity and in vivo release profile of sirolimus from implants into the vitreous of rabbits' eyes. Doc Ophthalmol 2019 Feb;138(1):3-19.
- Linares-Alba MA, Gómez-Guajardo MB, Fonzar JF, Brooks DE, García-Sánchez GA, Bernad-Bernad MJ. Preformulation Studies of a Liposomal Formulation Containing Sirolimus for the Treatment of Dry Eye Disease. J Ocul Pharmacol Ther 2016 Jan-Feb;32(1):11-22.
- Gografe SI, Hansen BC, Hansen KD. Deep subconjunctival injection of gentamicin for the treatment of bacterial conjunctivitis in macaques (Macaca mulatta and Macaca fascicularis). Lab Anim (NY) 2015 Mar;44(3):92-6.
- Nieto A, Hou H, Moon SW, Sailor MJ, Freeman WR, Cheng L. Surface engineering of porous silicon microparticles for intravitreal sustained delivery of rapamycin. Invest Ophthalmol Vis Sci 2015 Jan 22;56(2):1070-80.
- Wong WT, Dresner S, Forooghian F, Glaser T, Doss L, Zhou M, Cunningham D, Shimel K, Harrington M, Hammel K, Cukras CA, Ferris FL, Chew EY. Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci 2013 Apr 26;54(4):2941-50.
- Phillips BN, Wroblewski KJ. A retrospective review of oral low-dose sirolimus (rapamycin) for the treatment of active uveitis. J Ophthalmic Inflamm Infect 2010 Dec 7;1(1):29-34.
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