Pharmacokinetics, Electrophysiological, and Morphological Effects of the Intravitreal Injection of Mycophenolic Acid in Rabbits

Gasparin, Fabio; Aguiar, Renata Genaro; Ioshimoto, Gabriela Lourençon; Silva-Cunha, Armando; Fialho, Sílvia Ligório; Liber, Andre; Nagy, Balázs Vince; Oiwa, Nestor Norio; Costa, Marcelo Fernandes; Joselevitch, Christina; Ventura, Dora Fix; Damico, Francisco Max

doi:10.1089/jop.2013.0236

Cited by 8 publications

(4 citation statements)

References 52 publications

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“…The lens takes up even more of the globe in mice, where IVT injections are generally limited to volumes of up to 2 μl (Lin et al, 2014; Rösch et al, 2014; Du et al, 2015). Rabbits on the other hand have larger eyes, yet their lens still occupies ~40% of the axial length of the eye (Trivedi et al, 2002), which allows IVT injections of up to 50–100 μl (Chen et al, 2011; Gasparin et al, 2014). From the surgical standpoint, big lenses considerably restrict the space in which the needle can be safely maneuvered without damaging the retina or the lens and its capsule.…”

Section: Intravitreal Injectionmentioning

confidence: 99%

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

2017

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An exceptionally high number of monogenic disorders lead to incurable blindness, making them targets for the development of gene-therapy. In order to successfully apply therapeutic vector systems in vivo, the heterogeneity of the disease phenotype needs to be considered. This necessitates tailored approaches such as subretinal or intravitreal injections with the aim to maximize transduction of target cell populations, while minimizing off-target effects and surgical complications. Strategic decisions on parameters of the application are crucial to obtain the best treatment outcomes and patient safety. While most of the current retinal gene therapy trials utilize a subretinal approach, a deeper understanding of the numerous factors and considerations in choosing one delivery approach over the other for various ocular pathologies could lead to an improved safety and treatment efficacy. In this review we survey different vector injection techniques and parameters applied in recent retinal (pre-)clinical trials. We explore the advantages and shortcomings of each delivery strategy in the setting of different underlying ocular pathologies and other relevant factors. We highlight the potential benefits for patient safety and efficacy in applying those considerations in the decision making process.

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Section: Intravitreal Injectionmentioning

confidence: 99%

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

2017

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“…At 28 days after the LyeTx I b intravitreal injection, no alterations were detected. The analysis of the b-wave amplitude variation according to the luminous stimulus intensity is a widely used method for the functional evaluation of the retina [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Intravitreal injection of the synthetic peptide LyeTx I b, derived from a spider toxin, into the rabbit eye is safe and prevents neovascularization in a chorio-allantoic membrane model

Silva

Paiva

Dourado

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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BackgroundThe great diversity of molecules found in spider venoms include amino acids, polyamines, proteins and peptides, among others. Some of these compounds can interact with different neuronal receptors and ion channels including those present in the ocular system. To study potential toxicity and safety of intravitreal injection in rabbits of LyeTx I b, a synthetic peptide derived from the toxin LyeTx I found in venom from the spider Lycosa eritrognatha and to evaluate the angiogenic activity on a CAM model.MethodsARPE-19 cells were treated with LyeTx I b (0.36; 0.54; 0.72; 2.89; 4.34 or 9.06 μM). In this study, New Zealand rabbits were used. LyeTx I b (2.89 μM) labeled with FITC dissolved in PBS, or only PBS, were injected into vitreous humor. Electroretinogram (ERG) was recorded 1 day before injection and at 7, 14 and 28 days post-injection. Clinical examination of the retina was conducted through tonometer and eye fundus after ERG. Eyes were enucleated and retinas were prepared for histology in order to assess retinal structure. CAMs were exposed to LyeTx I b (0.54; 0.72; 2.17 or 2.89 μM).ResultsARPE-19 cells exposed to LyeTx I b showed cell viability at the same levels of the control. The fluorescence of LyeTx I b labeled with FITC indicated its retinal localization. Our findings indicate ERG responses from rats injected in the eye with LyeTx I b were very similar to the corresponding responses of those animals injected only with vehicle. Clinical examination found no alterations of intraocular pressure or retinal integrity. No histological damage in retinal layers was observed. CAM presented reduced neovascularization when exposed to LyeTx I b.ConclusionsIntravitreal injection of LyeTx I b is safe for use in the rabbit eye and prevents neovascularization in the CAM model, at Bevacizumab levels. These findings support intravitreal LyeTx I b as a good candidate to develop future alternative treatment for the retina in neovascularization diseases.

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“…No entanto, não existem muitos trabalhos realizados até o momento com MPA. Nosso grupo avaliou as alterações funcionais de diferentes doses de MPA (0,005, 0,05, 0,2 e 1mg/mL) após injeção intravítrea em coelhos Gasparin et al, 2014) e a farmacocinetica do MPA no vitreo (Gasparin et al, 2014 (Meira, Rocha & Oréfice, 2005).…”

Section: Lista De Ilustraçõesunclassified

“…Optamos pelo uso de animais albinos, pois relatos na literatura sugerem que a pigmentação possa ser um fator protetor contra efeitos tóxicos de algumas drogas, o que poderia mascarar ou diminuir os possíveis efeitos de toxicidade (Zemel et al, 1995;Bui;Sinclair;Vingrys, 1998;Perlman, 2009). Estas características explicam a razão pela qual a maior parte dos estudos de toxicidade retiniana de várias drogas por meio de injeção intravítrea foi realizada em coelhos (Kwak & D'amico,1992;Yu et al, 2006;Fauser et al, 2004;Ishikawa et al, 2006;Manzano et al, 2006;Gao et al, 2006Gasparin et al,2014). As doses intravítreas utilizadas atualmente, assim como as de antibióticos para o tratamento de endoftalmite, foram estabelecidas com base nos resultados de estudos experimentais em coelhos.…”

Section: Animal Experimentalunclassified

Estudo morfológico e eletrofisiológico dos efeitos da injeção intravítrea de ácido micofenólico em coelhos utilizando um modelo de uveíte crônica experimental

Liber¹

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Uveitis is an intraocular inflammation usually chronic and a major cause of blindness in the world. Corticosteroids are the first choice drug for treatment of non-infectious uveitis, but other immunosuppressive drugs are usually required. Mycophenolate mofetil is a powerful immunosuppressant orally administered that has been used successfully in the treatment of uveitis, but whose side effects often lead to the suspension of the drug intake. The Mycophenolate mofetil is a prodrug, which isconverted in the liver to mycophenolic acid (MPA), the active immunosuppressant. To minimize side effects of the use of mycophenolic acid and to enable a higher administration dose in the eye, we tested the effects of the intravitreal injection of mycophenolic acid in an experimental model of chronic uveitis (ECU) in rabbit eyes. The objectives of this study were: 1) to reproduce an ECU model in rabbits by intravitreal injection of M. tuberculosis; 2) to establish a safe dose of mycophenolic acid to be injected into the vitreous; and 3) to analyze the morphological, clinical and electrophysiological effects of the intravitreal injection of mycophenolic acid in rabbits used as a model of ECU. The ECU model reproduced showed a self-limiting inflammation, having a peak of inflammation at 17 days after uveitis induction. Both MPA doses we tested (0.1 and 1 mg) were not toxic to the retina. The ECU model received an intravitreal injection of 0.1 mg of MPA and clinical analysis demonstrated a reduction of the inflammation. The electroretinography (ERG) analysis also indicated an improvement in the inflammation process by restoring the latency of the a-wave and b-wave (photopic and scotopic) and by the recovery of the a-wave amplitude (photopic). The morphological analysis with HE showed no changes in the retinal structure, however the immunohistochemistry for GFAP protein showed gliosis of Müller cells, indicating an inflammatory process. We conclude that the ECU model reproduced an anterior uveitis similar to the human uveitis and the MPA dose we used showed therapeutic effects during the inflammation peak, reducing the inflammation and promoting the recovery of photoreceptors and ON bipolar cells. This makes intravitreal injections of MPA a promising resource in the treatment of uveitis. Future studies are necessary to standardize the present findings.

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Pharmacokinetics, Electrophysiological, and Morphological Effects of the Intravitreal Injection of Mycophenolic Acid in Rabbits

Abstract: MPA vitreous half-life is 5.0 days. Intravitreal injection of 0.5 μg MPA and higher causes dose- and time-related photoreceptor sensitivity decrease in rabbits. The MPA dose of 0.05 μg may be safe for intravitreal use in rabbits.

Cited by 8 publications

References 52 publications

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

Intravitreal injection of the synthetic peptide LyeTx I b, derived from a spider toxin, into the rabbit eye is safe and prevents neovascularization in a chorio-allantoic membrane model

Estudo morfológico e eletrofisiológico dos efeitos da injeção intravítrea de ácido micofenólico em coelhos utilizando um modelo de uveíte crônica experimental

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