Rabbit Intraocular Reactivity to Endotoxin Measured by Slit-Lamp Biomicroscopy and Laser Flare Photometry

Nussenblatt, Robert B.; Calogero, Don; Buchen, Shelley Y.; Leder, Henry A.; Goodkin, Margot L.; Eydelman, Malvina B.

doi:10.1016/j.ophtha.2012.04.004

Cited by 15 publications

(14 citation statements)

References 10 publications

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“…Several studies have demonstrated that the eye is uniquely sensitive to the effects of endotoxin contamination. 4,5 However, much of this work has focused on anterior segment and intracameral routes of administration of endotoxin-laden formulations or OVDs. Contamination following ITV injection of therapeutic agents is of concern due to the recent increase of intravitreal therapies.…”

Section: Discussionmentioning

confidence: 99%

“…The eye has been shown to be very sensitive to the effects of intracameral endotoxin and endotoxin-contaminated ophthalmic viscosurgical devices (OVDs). [3][4][5] The inflammatory effects of endotoxin are well described, and it is often used to produce experimental animal models of uveitis following ITV in mice, 6 rabbits, [7][8][9][10][11] pigs, 12 and monkeys. 13 Clinically, cases of acute postoperative sterile uveitis or toxic anterior segment syndrome have been linked to endotoxin contamination of ophthalmic devices.…”

mentioning

confidence: 99%

“…The purpose of this 43-day study was to define the response to intravitreal purified reference endotoxin levels of 0.01 to 0.75 endotoxin unit/eye (EU/eye) in Dutch Belted rabbits, including the definition of a no-observable effect level (NOEL) and the time course of the response in both the anterior and posterior segments of the eye. As mentioned above, adverse ocular effects following intracameral endotoxin and endotoxin-contaminated OVDs in rabbits have been described previously, [3][4][5] and generally was used as the basis for dose range selection in the current study.…”

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confidence: 99%

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Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits

Bantseev¹,

Miller

Bentley

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to characterize the inflammatory response and determine a no-observable effect level (NOEL) in rabbit eyes after endotoxin intravitreal (ITV) injection.METHODS. Fifty-three naïve male Dutch Belted rabbits were treated with a single 50-lL ITV injection ranging from 0.01 to 0.75 endotoxin units/eye (EU/eye) and monitored for up to 42 days post treatment. Ophthalmic examination included slit-lamp biomicroscopy and indirect ophthalmoscopy. Laser flare photometry was performed in a subset of animals. On days 2, 8, 16, and 43, a subset of animals was necropsied and eyes processed for histopathological evaluation.RESULTS. Intravitreal injection of endotoxin at ‡0.05 EU/eye resulted in a dose-related anterior segment inflammation response. No aqueous flare or cell response was noted in the 0.01 EU/ eye dose group. A more delayed posterior segment response characterized by vitreal cell response was observed beginning on day 5, peaking on day 9, and decreasing starting on day 16 that persisted at trace to a level of 1þ on day 43. Microscopy findings of infiltrates of minimal mixed inflammatory cells in the vitreous and subconjunctiva and proteinaceous fluid in the anterior chamber and/or vitreous were observed in eyes given ‡0.1 EU/eye. CONCLUSIONS.We defined the NOEL for ITV endotoxin to be 0.01 EU/eye, suggesting that the vitreal cavity is more sensitive to the effects of endotoxin than the anterior segment and aqueous chamber. These data highlight the importance of assessing endotoxin level in intravitreal formulations, as levels as low as 0.05 EU/eye may confound the safety evaluations of intravitreal therapeutics in rabbits.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits

Bantseev¹,

Miller

Bentley

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Nussenblatt et al (26) reported a 3-fold increase in flare values in rabbit eyes at 3 hours after LPS injection before decreasing 9 hours later. However, no significant changes in flaremetry were observed following endotoxin intravitreal injection in the present study.…”

Section: Discussionmentioning

confidence: 98%

“…The intravitreal route (26) was chosen in the present study as numerous ocular alterations related to other methods have been reported in previus studies. In corroboration with previous studies (26) in rabbits, the clinical signs associated with uveitis, such as conjunctival hyperemia, chemosis, blepharospasm, and ocular discharge, were also observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

Effects of morphine on the expression of cytokines and inflammatory mediators in a rabbit model of endotoxin-induced experimental uveitis

Ortencio¹,

Renzo²,

Sobrinho³

et al. 2015

Arquivos Brasileiros De Oftalmologia

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Purpose:To evaluate the effects of 1% morphine instillation on clinical parameters, aqueous humor turbidity, and expression levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1beta), prostaglandin E2 (PGE2), and myeloperoxidase (MPO) in rabbits with endotoxin-induced experimental uveitis. Methods: Twenty four New Zealand white rabbits were divided into four groups (n=6 each): control (CG), morphine (MG), naloxone (NG), and morphine-naloxone (MNG) groups. Under dissociative anesthesia, 0.1 mL of solution containing 0.2 μg of lipopolysaccharide (LPS) endotoxin from the Salmonella typhimurium cell wall was injected in the vitreous chamber. Clinical evaluations (conjunctical hyperemia, chemosis blepharospasm, and ocular discharge) and laser flaremetry were performed before (baseline), and 10 and 20 hours after induction of uveitis. Rabbits were subsequently euthanized and eyes were enucleated to quantify expression levels of TNF-α, IL-1 beta, PGE2, and MPO. Results: No significant differences in clinical parameters and flare values were observed between the study groups. TNF-α and IL-1 beta levels increased significantly in the CG, MG, NG, and MNG groups compared to baseline (P<0.05). Significant differences in PGE2 levels were observed between the MG and NMG groups (P<0.05). A trend toward increased MPO activity was observed in response to uveitis induction; however, this trend did not reach statistical significance (P>0.05). Conclusions: Morphine has no effect on clinical parameters, flare, or expression levels of inflammatory mediators in a rabbit model of uveitis induced by intravitreal injection of LPS.Keywords: Lasers/diagnostic use; Photmetry/methods; Morphine/administration & dosage; Endotoxins/toxicity; Uveitis/chemically induced; Rabbit RESUMO Objetivo: Estudaram-se os efeitos da instilação de morfina 1% sobre parâmetros clíni-cos, turbidez do humor aquoso e expressão de fator de necrose tumoral alfa (TNF-alfa), de interleucina-1 beta (IL-1beta), de prostaglandina E2 (PGE2) e de mieloperoxidase (MPO), em olhos de coelhos com uveíte induzida por endotoxina. Material e Métodos: Vinte e quatro coelhos da raça Nova Zelândia Branco foram distribuídos em quatro grupos (n=6, em cada): grupo controle (GC), morfina (GM), naloxona (GN) e morfina-naloxona (GMN

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Microbiological Considerations for Ophthalmic Products: Sterility, Endotoxin Limits, and Preservatives

Hasegawa

Gulmezian-Sefer

Cheng

et al. 2021

Ophthalmic Product Development

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Rabbit Intraocular Reactivity to Endotoxin Measured by Slit-Lamp Biomicroscopy and Laser Flare Photometry

Cited by 15 publications

References 10 publications

Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits

Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits

Effects of morphine on the expression of cytokines and inflammatory mediators in a rabbit model of endotoxin-induced experimental uveitis

Microbiological Considerations for Ophthalmic Products: Sterility, Endotoxin Limits, and Preservatives

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