Toxicity of High-Dose Intravitreal Adalimumab (Humira) in the Rabbit

Manzano, Roberta Munhoz; Peyman, Gholam A.; Carvounis, Petros; Damico, Francisco Max; Aguiar, Renata Genaro; Ioshimoto, Gabriela Lourençon; Ventura, Dora Fix; Cursino, Sylvia T.; Takahashi, Walter Yukihiko

doi:10.1089/jop.2010.0174

Cited by 19 publications

(17 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The administration of doses up to 5 mg of adalimumab produced no functional or structural ocular toxicity (16)(17)(18) . These studies evaluating adalimumab toxicity have, however, used electroretinography and histological methods, which cannot detect at sub-microscopic levels.…”

Section: Discussionmentioning

confidence: 93%

“…However, these studies used subcutaneous administration, which requires a higher drug concentration (40 mg) compared with the low dose applied intravitreously (0.5 mg). Higher doses of adalimumab, subcutaneously or intravitreously, may be the cause of increased cell apoptosis and in some cases even necrosis (16) .…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the use of intravitreal injection is the preferred method for treating ocular diseases because it provides higher drug concentrations with fewer injections of low dosage, preventing the risk of systemic exposure. However, few studies on the safety of intravitreal use of adalimumab have been published; for these, electroretinography and histological techniques have been used (14,(16)(17)(18) . These techniques cannot detect toxicity at the submicroscopic level and therefore we tested new methods to address intravitreal adalimumab toxicity at the cellular and molecular level in this study.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytotoxicity and genotoxicity of intravitreal adalimumab administration in rabbit retinal cells

Paula

Ávila

Isaac

et al. 2015

Arquivos Brasileiros De Oftalmologia

View full text Add to dashboard Cite

Purpose: To assess the cytotoxicity and genotoxicity of intravitreal adalimumab treatment in an animal experimental model using cytological and molecular te chniques. Methods: Eighteen rabbits were randomly assigned to three groups: control, adalimumab treatment, and placebo. Cytotoxicity on retinal cells was evaluated using flow cytometry assays to determine the level of apoptosis and necrosis. Genotoxicity was evaluated by comet assays to assess DNA damage, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate expression of apoptosis-inducing caspases (8 and 3). Results: No cytotoxicity or genotoxicity was observed in any of the two treatment groups (adalimumab and placebo) following intravitreal administration compared with the control group. Flow cytometry analysis revealed that more than 90% of the cells were viable, and only a low proportion of retinal cells presented apoptotic (~10%) or necrotic (<1%) activity across all groups. Molecular damage was also low with a maximum of 6.4% DNA degradation observed in the comet assays. In addition, no increase in gene expression of apoptosis-inducing caspases was observed on retinal cells by qPCR in both the adalimumab and placebo groups compared with the control group. Conclusion: The use of adalimumab resulted in no detectable cytotoxicity or ge notoxicity on retinal cells for up to 60 days upon administration. These results therefore indicate that adalimumab may be a safe option for intravitreal application to treat ocular inflammatory diseases in which TNF-α is involved.

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxicity and genotoxicity of intravitreal adalimumab administration in rabbit retinal cells

Paula

Ávila

Isaac

et al. 2015

Arquivos Brasileiros De Oftalmologia

View full text Add to dashboard Cite

show abstract

“…There is a large amount of clinical data regarding the efficacy of adalimumab as an anti-TNFα agent because it has been widely used for the treatment of systemic and chronic inflammatory conditions [12]. While this drug is not yet approved for human intravitreal injection, it has been tested in rabbits where it induced no retinal toxicity at a dosage of 0.5 mg/0.1 ml [13][14][15]. At higher doses, retinal inflammation and necrosis occurred.…”

Section: Discussionmentioning

confidence: 99%

Role of Systemic Anti-Tumor Necrosis Factor Alpha Treatment in the Reduction of Proliferative Vitreoretinopathy

Rosa¹,

Fernandez²,

Lipski³

2015

J Clin Exp Ophthalmol

View full text Add to dashboard Cite

Objective: Proliferative vitreoretinopathy (PVR) is still one of the most serious complications of rhegmatogenous retinal detachment (RRD) because there is no effective treatment or prophylaxis. Tumor necrosis factor α (TNFα) has been implicated in the development of PVR. Thus, the blockade of this factor could reduce or prevent the onset of PVR. However, systemic treatment with anti-TNFα has some risks and side effects, and the use of these drugs in this situation is not yet justified. Therefore we sought an indirect approach to determine if systemic anti-TNFα provided any protection against the development of PVR after RRD surgery. We attempted to estimate the rate of RRD and PVR in patients who were treated systemically with anti-TNFα drugs because of autoimmune diseases and who also had surgically-treated RRD.Methods: Nine centers participated in this retrospective, observational study of cases and controls. Two different approaches were used to find cases and controls. The records at five clinical centers of patients who were under anti-TNFα treatment for chronic inflammatory systemic diseases between January 2004 and 2014 were reviewed to determine how many developed RRD. Additionally, the records in eight clinical centers of patients who underwent RRD surgery during this same period were reviewed to determine the numbers who were simultaneously receiving anti-TNFα treatment. Cases included patients treated with anti-TNFα treatment whereas controls were those who were not under anti-TNFα treatment. Both patients and controls had systemic inflammatory disease. The main outcome measure was development of PVR after RRD surgery at three months follow-up.Results: A total of 8,017 medical records from nine different centers were reviewed. Among the 1,884 patients with anti-TNFα treatment and 6,133 patients operated for primary RRD, only 3 controls and 1 case were identified.Conclusions: An insufficient number of patients were identified to allow any valid conclusion regarding our hypothesis that systemic anti-TNFα therapy could reduce the onset of PVR after RRD surgery. Nevertheless, this indirect approach could be useful for future research in PVR prevention.

show abstract

“…The use of experimental models is important as there are many difficulties involved in getting intraocular tissue from patients' eyes, including technical and ethical issues. Experimental models are important for the development of new therapeutic agents as they are useful to evaluate the efficacy and toxicity of systemic and intravitreous drug delivery, such as antibiotics (3)(4)(5) , corticosteroids (6,7) , immunosuppressive drugs (8,9) , and more recently anti-VEGF (10,11) , and biological agents (e.g., tacrolimus, sirolimus, etanercept, infliximab, adalimumab, and rituximab) (12)(13)(14)(15)(16)(17)(18)(19) . The aim of this paper is to review the most used experimental autoimmune ocular inflammatory diseases models used in Ophthalmology and their most important aspects.…”

Section: Introductionmentioning

confidence: 99%

Experimental models of autoimmune inflammatory ocular diseases

Gasparin¹,

Takahashi²,

Scolari³

et al. 2012

Arq. Bras. Oftalmol.

Self Cite

View full text Add to dashboard Cite

Toxicity of High-Dose Intravitreal Adalimumab (Humira) in the Rabbit

Abstract: Intravitreous adalimumab exhibited no associated ocular short-term toxicity in rabbit eyes up to the 5 mg dose. In the 10 mg group mild clinical findings and ERG amplitude reduction could reflect early toxicity.

Cited by 19 publications

References 19 publications

Cytotoxicity and genotoxicity of intravitreal adalimumab administration in rabbit retinal cells

Cytotoxicity and genotoxicity of intravitreal adalimumab administration in rabbit retinal cells

Role of Systemic Anti-Tumor Necrosis Factor Alpha Treatment in the Reduction of Proliferative Vitreoretinopathy

Experimental models of autoimmune inflammatory ocular diseases

Contact Info

Product

Resources

About