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A Study of Retinal Penetration of Intravitreal Tenecteplase in Pigs

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A Study of Retinal Penetration of Intravitreal Tenecteplase in Pigs A Study of Retinal Penetration of Intravitreal Tenecteplase in Pigs Anthony S. L. Kwan, Sarojini Vijayasekaran, Ian L. McAllister, Paula K. Yu, and Dao-Yi Yu PURPOSE. To determine the degree of retinal penetration of Toxicity profiles for tPA injected intravitreally were estab- intravitreal tenecteplase in a porcine model. lished in both rabbit16 and cat17,18 retina. In humans, retinal ETHODS ␮ toxicity is variable and toxic effects have been reported at what M . Fluorescence-tagged tenecteplase (50 g in 0.1 mL 19,20 physiologic saline) was injected into the vitreous of the right is considered by some to be therapeutic doses. Recently, a and left eyes at 24 and 6 hours before death, respectively, in six third-generation thrombolytic agent has been developed to nonvitrectomized pigs. Retinal penetration was assessed on address some of the shortcomings of tPA. Tenecteplase (TNK) frozen sections by epifluorescence microscopy and statistical is a variant of native tPA that has been produced by recombi- nant DNA technology, having undergone multiple-point muta- analysis was performed. Frozen sections of two eyes without 21,22 injection (control) were also assessed. tions at the T, N, and K domains. TNK has been tested extensively in clinical trials23–25 for the treatment of myocar- RESULTS. Labeling of fluorescence-tagged tenecteplase was seen dial infarction. The issue of retinal toxicity of intravitreal TNK in all the layers of the retina at both time points with more 26 Ͻ has been addressed in a previous study. Doses of up to 100 intense signal at 24 hours after injection (P 0.05). ␮g TNK appear to be safe for intravitreal injection in rabbits, CONCLUSIONS. Fluorescence-tagged tenecteplase can penetrate with no evidence of retinal toxicity. These data suggest a wider all the layers of the retina of porcine eyes after intravitreal therapeutic window for TNK than for tPA and may indicate injection. Intravitreal tenecteplase may be useful in the in the that higher doses of TNK can be used, which may be more management of subretinal hemorrhage. (Invest Ophthalmol effective in dissolving thicker SRHs. Vis Sci. 2006;47:2662–2667) DOI:10.1167/iovs.05-1019 The purpose of this study was to determine whether TNK can pass through the retina to reach the subretinal space after ubmacular hemorrhage (SRH) is a serious event that may be intravitreal injections into nonvitrectomized eyes in a porcine Scaused by several conditions including trauma, retinal mac- model. roaneurysm, age-related macular degeneration (AMD), high myopia, and complications of vitreoretinal surgery.1 The natu- ral history of SRH is variable. Visual recovery may be good in MATERIALS AND METHODS some cases; however, the prognosis is generally poor for large, thick SRHs and those associated with AMD.2–5 Several methods All animal procedures were approved by the Animal Ethics Committee have been described for the treatment of SRH, including pneu- of the University of Western Australia and conformed to the ARVO matic displacement, with6,7 or without8 adjunctive treatment Statement for the Use of Animals in Ophthalmic and Vision Research of tissue plasminogen activator (tPA), and vitrectomy surgery and the policies in the Guide to the Care and Use of Laboratory Animals with drainage of SRH, with9–11 or without tPA.12,13 tPA is a of the National Institutes of Health. naturally occurring endogenous serine protease with a molec- Seven pigs (ϳ10 kg each) aged 4 weeks were used in the study. Six ular mass of 70 kDa.14 It forms a complex with fibrin to activate pigs received bilateral intravitreal fluorescence-conjugated TNK injec- plasminogen to plasmin, which, in turn, lyses fibrin and other tions in a two-stage procedure, with the right and left eyes receiving procoagulant proteins into soluble degradation products, thus injections 24 and 6 hours before death, respectively. The right eye was dissolving the blood clot. Through dissolution of fibrin, tPA is injected first, followed by the left eye 18 hours later. Fluorescence- believed to reduce the fibrin-mediated clot’s adherence to the labeled TNK was injected into the midvitreous cavity under direct retina and thus to decrease photoreceptor damage during the vision through the operating microscope and contact lens. TNK (Me- removal of SRH. It is unclear, however, how tPA penetrates the talyse; Boehringer Ingelheim, NSW, Australia) was conjugated with a retina to reach the subretinal clots when it is used intravitreally superior, highly photostable green fluorescent dye, AlexaFluor 488 and without direct injection into the subretinal space. Further- (C39H44N8Na2O13S3), with an excitation and emission maxima of 495 more, the ability of tPA to diffuse through the retina and into and 519 nm (custom synthesis of TNK by Invitrogen [Eugene, OR] for the subretinal space has been questioned in an experimental Invitrogen Australia Pty Ltd). Conjugation was performed according to 15 model.15 the method described by Kamei et al., in which the L-arginine (vehi- cle) of tPA was replaced with N-acetyl arginine, conjugated with the dye and thereafter separated with L-arginine as the eluting solvent. From the Lions Eye Institute, Centre for Ophthalmology and Visual Six of the pigs were sedated with an intramuscular injection of 4.4 Science, the University of Western Australia, Nedlands, Australia. mg/kg Zoletil 100 (250 mg Tiletamine and 250 mg Zolazepam; Virbac Supported by the National Health and Medical Research Council Laboratories, Ltd., Peakhurst, NSW, Australia). The animals were then of Australia and the Ophthalmic Research Institute of Australia. masked and maintained on halothane, oxygen, and nitrous oxide. The Submitted for publication August 3, 2005; revised November 16 pupils were dilated with 2.5% phenylephrine hydrochloride and 1% and December 15, 2005; accepted March 27, 2006. tropicamide. A 26-gauge needle was introduced into the vitreous cavity Disclosure: A.S.L. Kwan, None; S. Vijayasekaran, None; I.L. transsclerally, 2 to 3 mm posterior to the superotemporal limbus and McAllister, None P.K. Yu, None; D.-Y. Yu, None under direct vision through a planoconcave contact lens and an oper- The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertise- ating microscope. The needle bevel was visualized in the midvitreous ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. cavity and 0.1 mL of the fluorescence-TNK conjugate at a concentra- Corresponding author: Ian L. McAllister, Lions Eye Institute, Cen- tion of 50 ␮g/0.1 mL physiologic saline solution was injected into each tre for Ophthalmology and Visual Science, The University of Western eye at the specified time points. To ensure the stability of the fluores- Australia, Nedlands, WA 6009, Australia; [email protected]. cence–TNK conjugate, the drug was freshly diluted just before injec- Investigative Ophthalmology & Visual Science, June 2006, Vol. 47, No. 6 2662 Copyright © Association for Research in Vision and Ophthalmology Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/932938/ on 02/09/2017 IOVS, June 2006, Vol. 47, No. 6 Tenecteplase Retinal Penetration 2663 FIGURE 1. Epifluorescence micro- graphs of a frozen section of a nor- mal porcine retina taken from the posterior pole, as seen through a fluorescence-detection filter. Auto- fluorescence label was yellow in a linear configuration along the reti- nal pigment epithelium (RPE), brown in the rod outer segments (double arrow) and red blood cells (arrow) within the retinal and cho- roidal blood vessels, and faint green in the outer nuclear layer (ONL) of the photoreceptor cells, choroid, and sclera (SC). tion. The needle was left in situ for a further 20 seconds after injection On examination of the frozen sections through a fluores- it was withdrawn, to avoid reflux from the entry site. Chloramphenicol cence-relevant detection filter, autofluorescence was observed ointment 1% (Chlorosig; Sigma Pharmaceuticals Ltd., Castle Hill, Aus- in all the eyes, including those injected with fluorescence- tralia) was applied to the eyes after surgery, and the pigs were allowed labeled TNK and in the control eye without injection. Autofluo- to recover before death. One normal pig without injection was used as rescence appeared yellow in a linear configuration along the the control. retinal pigment epithelium, brown in the rod outer segments For histologic analysis, all the experimental and control eyes were and red blood cells within the retinal blood vessels, and a faint enucleated and fixed in 4% paraformaldehyde for 24 hours at 4°C. Four green in the outer nuclear layer choroid and sclera. Autofluo- retinal samples, each measuring 3 mm2, were taken from the posterior rescence of the sclera was more marked. pole of each eye. The samples were embedded in optimal cutting In the control animal, Autofluorescence was observed in temperature compound (OCT; Pro Sci Tech Pty Ltd., Kirwan, Queens- both eyes (Fig. 1). At 6 hours after injection (left eyes), in land, Australia) in frozen blocks. Ten-micrometer-thick sections were addition to autofluorescence, a weak fluorescent signal (grade cut on a cryostat (CM 3050S; Leica, Heidelberg, Germany). Sections 1) was observed in four of the six eyes in all the layers of the were analyzed and photographed without performing any other pro- retina, including the inner limiting membrane, ganglion cell cedures in order to avoid washing away labeled protein/TNK. The layer, inner nuclear layer, photoreceptor cell layer, and plexi- distribution of the labeled protein was visualized under an epifluores- form layers. The signal was more pronounced at the level of cence microscope equipped with a fluorescence-relevant detection the inner segments of the photoreceptor cell layer, along the filter (excitation and emission maxima 495 and 519 nm). To ensure internal limiting membrane (ILM) and matrix surrounding the that the fluorescence distribution and intensity are related only to the retinal ganglion cell axons.
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