Ocular toxicity of intravitreal clarithromycin.

OBJECTIVE: To investigate the ocular toxicity and clearance of intravitreal clarithromycin lactobionate (Klaricid) and to determine the highest nontoxic dose. MATERIALS AND METHODS: To evaluate toxicity, 24 New Zealand white rabbits were divided into six groups (four rabbits each). Rabbits were examined preoperatively and electroretinography (ERG) was performed. The left eyes of the animals served as controls and received intravitreal injection of 0.1 mL sterile water. Klaricid (0.1 mL) was injected into the midvitreous cavity of the right eyes at concentrations of 25 microg, 250 microg, 500 microg, 1.0 mg, 2.0 mg, and 4.0 mg/0.1 mL. The animals were followed up to 15 days postinjection by clinical examination and ERG. The animals were killed and the eyes were enucleated and processed for light microscopy. Ten New Zealand rabbits were used for the vitreous clearance study as drug test rabbits and two additional rabbits were used to generate control retina and vitreous. The highest nontoxic dose (1 mg) was injected into the vitreous and the concentration of clarithromycin in the vitreous was determined using high-performance liquid chromatography at various time intervals after injection. RESULTS: Cataract occurred after intravitreal doses of 2.0 and 4.0 mg. Electroretinography showed decreasing b-wave amplitude with both dark- and light-adapted stimulus in the 4.0-mg group; it was normal in other groups. Histopathologic sections showed localized retinal necrosis and disorganization with the 2.0 and 4.0 mg dosage. No histologic changes were found in the other groups. The half-life of intravitreal clarithromycin was found to be 2 hours. No metabolites of clarithromycin were observed in the vitreous samples. CONCLUSION: Intravitreal clarithromycin lactobionate is nontoxic to rabbit eyes up to a dose of 1.0 mg. Because of its broad-spectrum antibiotic effect and appropriate half-life in the vitreous, it may be a good choice for intravitreal treatment of susceptible organisms.     

Intravitreal toxicity of high-dose etanercept.

PURPOSE: The aim of this study was to evaluate the retinal toxicity of high-dose intravitreal etanercept, a U.S. Food and Drug Administration-approved anti-inflammatory drug, in the rabbit model. METHODS: Twenty (20) New Zealand albino rabbits were divided into 5 groups (n=4); eyes in each group were intravitreally injected with one of the following doses of etanercept: 125 microg, 250 microg, 500 microg, 1 mg, or 2.5 mg. One (1) eye in each animal was used for the study dose; the fellow eye was injected with buffered sterile saline as a control. All animals were examined using indirect ophthalmoscopy and slit-lamp biomicroscopy before and after intravitreal injection and at days 1, 7, and 14. Electroretinography (ERG) was performed on all animals before intravitreal injection and 14 days after injection. The animals were euthanized on day 14. Histological preparations of the enucleated eyes were examined with light microscopy for retinal toxicity. RESULTS: Clinical examination, histological evaluation, and ERG results of all 5 groups demonstrated no signs of retinal toxicity. CONCLUSIONS: Intravitreal doses as high as 2.5 mg of etanercept did not cause retinal toxicity. Intravitreal doses of up to 2.5 mg of etanercept may provide a more potent, prolonged effect than the lower doses previously recommended.     

Intravitreal moxifloxacin: retinal safety study with electroretinography and histopathology in animal models

PURPOSE: To determine whether moxifloxacin can be used safely as an intraocular antibiotic, retinal safety of intravitreal moxifloxacin was studied with electroretinography (ERG) and histopathology in animal models. METHODS: Moxifloxacin was injected into mouse eyes at intravitreal concentrations of 5 to 500 microg/mL and into rabbit eyes at 150 microg/mL. As the control, the vehicle was injected into the fellow eyes of each animal. Four weeks after injection, ERG recordings were performed, and animal eyes were processed for histologic examination. RESULTS: ERG studies showed no significant difference between control and moxifloxacin-injected eyes at any dose in either the mouse or rabbit model. Histologic examination revealed no retinal abnormality in mice at 5 to 100 microg/mL or in rabbits at 150 microg/mL intravitreal moxifloxacin. In mice at 500 microg/mL, occasional focal retinal necroses were observed, suggesting isolated retinal toxicity at this concentration of moxifloxacin. CONCLUSIONS: Intravitreal moxifloxacin, up to 100 microg/mL in mice or 150 microg/mL in rabbits, caused no ERG or retinal histologic abnormality. These results indicate that moxifloxacin is a safe intravitreal antibiotic in mouse and rabbit animal models. If proven safe and efficacious by further study in humans, intravitreal injection of moxifloxacin could be considered as an alternative to currently used antibiotics in selected patients with resistance or allergy to the more traditional antibiotics.     

t-PA对实验性玻璃体渗出的治疗作用

18只兔眼玻璃体腔内注射自体血浆0.2ml制成的玻璃体渗出模型，随机接受玻璃体内注射组织型纤溶酶原激恬酶(t-PA)或生理盐水，其中10眼玻璃体内注入t-PA 12.5μg，结果6眼的纤维蛋白在6h内清除，另4眼在1d内彻底清除．注入生理盐水的7眼需7d才完全清除。两用从时间上比较，差别有显著性(P<0.05)．经裂隙灯、ERG、光镜及电镜检查未见毒性作用．另1只注入10μg t-PA的兔眼虽然6h内见纤维蛋白凝块溶解，但眼底镜和光镜下已显示视网膜的毒性变化。 （中华眼底病杂志，1994，10：14-16）     

兔眼玻璃体腔注射抗血管内皮生长因子单克隆抗体Bevacizumab的视网膜毒性研究

目的 观察不同剂量抗血管内皮生长因子单克隆抗体Bevacizumab兔眼玻璃体腔注射的视网膜毒性作用。 方法 16只新西兰无色素兔的32只眼随机分为药物注射组和对照组，药物注射组又根据玻璃体腔注射药物剂量不同分为A、B、C组，玻璃体腔注射Bevacizumab剂量分别为0.05、0.10、0.25 ml，分别含Bevacizumab 1.25、2.50、6.25 mg。对照组玻璃体腔注射0.9％生理盐水0.10 ml。注药后1、2、4周行视网膜电图（ERG）检查。另外 ，在兔眼玻璃体腔注射Bevacizumab后1、2、4周，每组各摘除2只兔眼，行视网膜组织形态及超 微结构的光学显微镜和透射电子显微镜观察。 结果 兔眼玻璃体腔注射 Bevacizumab后1、2、4周，兔眼ERG各项反应波形均正常，振幅均未出现异常改变（P＞0.05）。光学显微镜下观察 ，药物注射组和对照组视网膜各层组织形态在各时间点均未见异常。透射电子显微镜观察， A、B组与对照组无明显差异；C组视网膜光感受器细胞出现部分线粒体损伤，发生肿胀和积 水变，4周时病变无缓解。 结论 单次兔眼玻璃体腔注射Bevacizumab 1.25 mg或2.50 mg是安全的。 （中华眼底病杂志，2008，24：193-196）     

The effects of indocyanine green and endoillumination on rabbit retina: an electroretinographic and histological study

AIM: To evaluate the functional and morphological retinal toxicity associated with intravitreal injection of indocyanine green (ICG) dye in rabbit eyes during vitrectomy with endoillumination. METHODS: 20 eyes of 10 New Zealand pigmented rabbits were used in the study. All eyes underwent pars plana vitrectomy and removal of posterior vitreous cortex under endoillumination. In one eye of each rabbit, intravitreal injection of 0.1 ml of 2.5 mg/ml ICG was applied for 30 seconds followed by 10 minutes of endoillumination. The control eye had endoillumination only without ICG injection. Dark adapted and light adapted electroretinograms (ERGs) were performed before the surgery and 1 week after surgery for serial comparisons. Rabbits were killed 1 week after surgery and eyes were enucleated for histological examination. RESULTS: Serial ERG comparisons showed significant reduction in the light adapted a-wave amplitude (p = 0.037) and significant delays in the dark adapted and light adapted b-wave latencies (p = 0.020 and p = 0.038, respectively) in the ICG treated eyes. Histological examinations demonstrated loss of photoreceptor outer segments with focal absence of photoreceptors in some areas in the ICG injected eyes. CONCLUSIONS: Vitrectomy followed by intravitreal injection of 2.5 mg/ml ICG for 30 seconds with endoillumination may result in retinal toxicity causing functional and morphological retinal damages in rabbit eyes. The lowest concentration of ICG should be used if necessary for intraocular use to prevent potential retinal toxicity.     

Effects of intraocular irrigation with melphalan on rabbit retinas during vitrectomy

Purpose To investigate the toxic effects of perfusion of intravitreal melphalan during vitrectomy on the rabbit retina. Methods We performed electoretinography (ERG) in 18 eyes of 18 healthy albino rabbits before and after intraocular melphalan perfusion at concentrations of 5-, 10-, and 20-μg/ml during pars plana vitrectomy. Fellow eyes that underwent vitrectomy without melphalan served as controls. The histopathologic retinal changes were observed in both eyes of two rabbits from each group. Results In the 5-μg/ml perfusion group, the ERGs and histology showed no substantial changes compared with control fellow eyes during 28 days postoperatively. In the 10- and 20-μg/ml groups, the mean a-wave amplitude decreased to 52% and 31% respectively of the fellow eye; the mean b-wave amplitude decreased to 52% and 19% respectively. However, the peak implicit time of the a- and b-waves did not significantly differ in the 10- and 20-μg/ml groups during 28 days postoperatively. Histologic sections showed necrosis of the inner nuclear layer and thinning of the outer nuclear layer in the 10-μg/ml group. Loss of the outer nuclear layer and the photoreceptor layer and necrosis of the inner nuclear layer were observed in the 20-μg/ml group. Conclusion The intravitreal 5-μg/ml melphalan perfusion during vitrectomy appears to be nontoxic to the retina. This therapeutic modality might be a potential treatment for retinoblastoma with vitreous seeding. Grant Support: Supported in part by a grant from the Health and Welfare Ministry, Japan.     

Intravitreal toxicity of garenoxacin

PURPOSE: To assess the retinal toxicity of varying concentrations of intravitreally injected garenoxacin. METHODS: Twenty eyes of 20 New Zealand albino rabbits were used for this study. The animals were anesthetized with ketamine (35-50 mg/kg) and xylazine (3-5 mg/kg). Garenoxacin was titrated using distilled water to the following concentrations: 4,000, 2,000, 1,000, 400, 200, and 100 microg/0.1 mL. Each concentration was injected intravitreally (0.1 mL) into three rabbit eyes. Three control eyes were injected with 0.1 mL of balanced saline solution. All animals were examined before and after injection by indirect ophthalmoscopy and slit-lamp biomicroscopy. Electroretinography was performed on all animals before intravitreal injection and 14 days after injection. The animals were examined by indirect ophthalmoscopy and slit-lamp biomicroscopy before they were killed; the eyes were enucleated and examined with light microscopy. RESULTS: No electroretinographic changes or signs of retinal toxicity by slit-lamp examination, indirect ophthalmoscopy, or light microscopy were seen in any eyes 14 days after intravitreal injection of garenoxacin (< or =4,000 microg/0.1 mL). CONCLUSIONS: Garenoxacin injected intravitreally appeared safe at concentrations of < or =4,000 microg/0.1 mL.     

环孢霉素A微球兔眼玻璃体内注射的毒性研究

目的 研究一种新型的嵌段聚酯高分子化合物（ε－已丙酯－D，L－丙交酯嵌段共聚物）将环孢霉素A（CsA）包封制备成微球，兔眼玻璃体注射后对视网膜和视功能的毒性。方法 采用10只有色兔，玻璃体注射前行间接检眼镜眼底检查及眼电生理检查（ERG）均正常。含有750μgCsA的5mg微球以注射用生理盐水混悬，在间接检眼镜观察下注射到每只兔的左眼玻璃体腔中部，同样剂量的空白微球注射到右眼对照眼玻璃体中央。在注射后的不同时间点进行ERG检查。处死动物，摘取眼球对视网膜行组织学检查，并检查眼底至8周。结果 注射后1－2周时，平均的b波明显被抑制（P＜0．05），最大的暗适应ERG抑制出现在第1周。实验眼与对照眼的b波振幅比率为49．5％。ERG值在第4周基本恢复正常。b波的潜伏值在暗适应条件下为正常。a波振幅值和潜伏值在暗适应条件下实验眼与对照眼没有明显差异。组织学检查显示实验眼与对照眼的视网膜在第6周时没有明显改变。结论 玻璃体内注射可降解微球可以安全地将CsA传递至兔眼的后节段。     

Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment in the rabbit

PURPOSE: To investigate whether intravitreal injection of hyaluronidase can induce posterior vitreous detachment (PVD) in the rabbit. METHODS: One eye each of 12 New Zealand white rabbits received intravitreal injection via the pars plana of 20 IU of hyaluronidase (0.1 mL reconstituted in sterile balanced salt solution [BSS]) into the midvitreous cavity. The fellow eye of each rabbit received a vitreous injection of 0.1 mL of BSS. At 3 and 6 months after intravitreal injection, four and eight rabbits were killed, respectively, and the eyes were enucleated. After fixation, scanning electron microscopy was performed to study the vitreoretinal interface. RESULTS: At 3 and 6 months after injection, scanning electron microscopy showed that the retinal surfaces in eyes that received either hyaluronidase or BSS were covered with vitreous collagen fibers. No eyes, even those that received hyaluronidase over a period of 6 months, had the smooth retinal surface consistent with a bare internal limiting lamina that suggests the development of PVD. CONCLUSION: Hyaluronidase cannot induce PVD in the rabbit over a 6-month period after vitreous injection.     

Intraocular levels of cefuroxime in uninflamed rabbit eyes

Intraocular levels of cefuroxime following subconjunctival, intravitreal and combined intravitreal and intravenous administration were determined in uninflamed rabbit eyes. Intraocular levels of the antibiotic were assayed by a biological method. Penetration of cefuroxime into the vitreous following subconjunctival administration was poor. Subconjunctival administration produced higher levels of cefuroxime in the aqueous when compared to parenteral administration alone. Higher levels of cefuroxime were achieved both in the aqueous and in the vitreous after an intravitreal injection. Intravitreal injection of 100 and 1000 micrograms cefuroxime produced intravitreal levels close to the minimum inhibitory concentration (MIC) for most ocular pathogens up to 24 h after drug administration. Intravenous supplementation did neither enhance the intraocular levels nor did it delay the clearance of the intravitreally injected antibiotic. Mild histopathological changes were seen with equal frequency both in the control and the test eyes and are attributed to the sampling techniques. Electroretinography (ERG) showed no definite changes suggestive of retinal toxicity up to 55 days after intravitreal administration.     

兔眼玻璃体腔注射抗血管内皮生长因子单克隆抗体Bevacizumab的毒性观察

目的 观察不同剂量的抗血管内皮生长因子单克隆抗体Bevacizumab玻璃体腔注射后对兔眼角膜、房角、视网膜组织结构和功能的影响。 方法 24只健康新西兰大白兔分成3组，每组兔眼右眼分别注射Bevacizumab 1.25、2.50、5.00 mg；左眼为对照眼，注射相同体积的0.9％生理盐水。注射药物前后裂隙灯显微镜及直接检眼镜检查眼前段和眼底，监测眼压。注药前以及注药后1、4、8周行闪光视网膜电图（ERG）检查。8周时行角膜内皮计数后，摘除眼球行光学显微镜及透射电子显微镜检查。 结果 3组兔眼注射药物前后各时间点眼压、角膜内皮计数、ERG的a、b波振幅差异无统计学意义（P＞0.05）。光学显微镜检查，3组兔 眼角膜、房角、视网膜结构无明显变化。透射电子显微镜检查，视网膜超微结构亦无明显变化。 结论 玻璃体腔内注射1.25～5.00 mg Bevacizumab对正常兔眼组织没有明显毒性。 （中华眼底病杂志，2008，24：189-192）     

Increased retinal toxicity of intravitreal tissue plasminogen activator in a central retinal vein occlusion model

Background Intravitreal injection of tissue plasminogen activator (tPA) is used to treat several ocular conditions, although excessive doses of intravitreal tPA cause retinal toxicity. Toxicity may increase in the ischemic retina, such as in central retinal vein occlusion (CRVO), because tPA toxicity to neural tissues increases under ischemic conditions. We investigated tPA toxicity to the retina in a CRVO rat model. Methods CRVO was induced in pigmented rats with rose Bengal-assisted laser photothrombosis. One hour after CRVO induction, 3 μl of tPA (0.075, 0.75, 3, or 7.5 μg) was injected intravitreally. Eyes that did not receive laser treatment, which served as non-CRVO controls, received tPA (0.75, 3, or 7.5 μg). The same amount of balanced salt solution (BSS) was injected as a nondrug control. Eyes were enucleated at 12 hours after injection, and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) staining was performed to evaluate retinal cell apoptosis. Results The number of TUNEL-positive cells increased in a dose-dependent manner in both non-CRVO and CRVO group and significantly (P = 0.002) increased when 0.75, 3, or 7.5 μg of tPA was injected into the CRVO eyes. When comparing the number of TUNEL-positive cells between the eyes with and without CRVO that received the same treatment, apoptosis significantly increased in CRVO eyes. Conclusions Retinal toxicity associated with intravitreally injected tPA can increase in a dose-dependent manner and be exacerbated in CRVO eyes, suggesting that the dose of tPA should be reduced when tPA is used to treat eyes with CRVO. This study was presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Fla., May 1, 2006. The authors have no proprietary interest in any aspect of this study. Supported by a Grant-in-Aid for Scientific Research (#15591853) from the Ministry of Education, Science and Culture of Japan.     

Safety of intravitreal triamcinolone acetonide:an electrophysiologic and histopathological study in rabbits

AIM: To evaluate the retinal safety of various doses of intravitreal triamcinolone acetonide (TA) in rabbits.Methods: Thirty New Zealand albino rabbits were divided into five groups (six animals each). In group 1 (control group), each animal received a single intravitreal injection of 0.1mL phosphate buffered saline. In groups 2, 3, 4 and 5, each rabbit received a single intravitreal injection of 4, 8, 16 and 32mg of TA, respectively. Each dose was contained in 0.1mL phosphate buffered saline. Clinical ocular examinations were performed before the injection and on the 1st, 3rd, 10th and 17th post-injection days. A standard dark adapted electroretinogram (ERG) was obtained before injection and on the 3rd, 10th and 17th post-injection days. After 17d, animals were sacrificed and their eyes prepared for pathological examination.RESULTS:By monitoring ERG as a functional index for the retina, intravitreal injection of 4mg TA showed no significant ERG changes. At doses of 8, 16 and 32, hyper-abnormal responses in a- and b- waves of ERG were detected on the 3rd post-injection day. These changes gradually returned back to normal limits after 17d. Histopathological examination of the retina of all animals showed no pathological changes.CONCLUSION: High doses of intravitreal TA seemed to have enhancing effects on the retinal function with gradual return to normal limits with no pathological changes detected in examined eyes.     

Experimental intravitreal application of trovafloxacin in rabbits.

This study was performed to examine the retinal toxicity of trovafloxacin, a broad-spectrum fourth-generation fluoroquinolone, in rabbit eyes after intravitreal injection. The left eyes of 20 albino rabbits were divided into four groups, and each was injected intravitreally with 0.1 ml of trovafloxacin in a 50-microg, 100-microg, 250-microg or 500-microg concentration. The right eyes of these rabbits served as control and received normal saline solution. Retinal function was assessed from the electroretinogram (ERG), and retinal structure was also examined by ophthalmoscopy and histologic study (light microscopy). The intravitreal injections of 50 microg, 100 microg, and 250 microg trovafloxacin did not significantly change the ERG a-wave, b-wave or the oscillatory potential throughout the follow-up period of 4 weeks. While no ERG changes were observed at 4 weeks after injection, in the 3 eyes that received trovaloxacin 500 microg/0.1 ml, the a-wave amplitudes showed a diminution of 56-49% and those of b-waves one of 53-44% of the preinjection amplitudes at 4 weeks after injection, but oscillatory potentials remained unchanged in the other 2 rabbits intravitreally injected with 500 microg trovafloxacin. However, in none of the injected eyes and the control eyes in all groups were ophthalmoscopically visible fundus changes and histologic abnormality observed. The results suggest that intravitreally injected trovafloxacin at a dose of up to 500 microg is nontoxic to the rabbit retina. If future studies in other species confirm our findings, intravitreal trovafloxacin may be a good alternative in the treatment and prevention of clinical bacterial endophthalmitis.     

Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas

· Purpose: To assess the effects of intravitreal injection of recombinant tissue plasminogen activator (rTPA) and gas on submacular hemorrhage in age-related macular degeneration (ARMD). · Methods: Eleven consecutive patients (11 eyes) with subretinal hemorrhage due to ARMD involving the fovea with elevation of the neurosensory retina were included in this study. Subretinal hemorrhage occured 12 h to 14 days before onset of therapy. Injection of rTPA through the pars plana in a dose of 50 or 100 μg was performed. Gas instillation (0.2–0.4 ml) followed rTPA injection, either immediately after injection (7 patients) or during the following day (4 patients). · Results: After intravitreal injection of rTPA, subretinal clots were totally or partially liquefied when treatment started up to 3 days after onset of bleeding. In all patients treated with 100 μg rTPA a large exudative retinal detachment of the inferior retina resulted, which reabsorbed spontaneously within 2 weeks. After reattachment of the exudative retinal detachment hyperpigmentation of the retinal pigment epithelium was noted. Temporary opacification of the vitreous was observed between the 2nd and 7th postoperative day in 5 eyes (45.5%). Postoperative visual acuity increased in 5 patients (45.5%). · Conclusion: Intravitreal application of rTPA followed by gas injection is a sufficient and convenient technique for effective removal of freshly formed submacular hemorrhage. Removal is mediated through combined enzymatic (rTPA) and mechanical (gas) effects. This technique offers a quick recovery of vision in eyes with less severe ARMD. Received: 5 January 1998 Revised version received: 25 March 1998 Accepted: 23 June 1998     

Cyclosporine玻璃体腔内注射对异种视网膜色素上皮移植的排异抑制作用

目的 观察兔眼视网膜下腔植入人胚眼视网膜色素上皮（retinal pigment epithe-lium,RPE）后不同时期的眼底和组织学改变。研究环胞菌素A（Cyclosporines,CsA）玻璃体腔内注射能否抑制人胚眼RPE在兔眼视网膜下腔中诱导的异种移植排异反应。方法 人胚眼色素上皮片和浓缩色素上皮细胞悬液植入36只兔眼的视网膜下腔,其中16眼为对照组,用于观察排异的自然转规。分别7d(8眼）和30d(8眼）后获取组织标本。另20眼为实验组。RPE移植后,每周一次玻璃体腔内注射CsA 1mg(12眼）或CsA0.1mg(8眼）。视网膜和视神经的毒性反应使用ERG进行检查。结果 人胚眼RPE片和浓缩的RPE细胞均能在视网膜下腔短期存活。移植的RPE与视细胞结合良好并显示吞噬功能。排异反应发生时间约在术后10～30d。对照组中7d的排异发生率为0/8;30d排异发生率为7/8。排异发生后荧光造影中移植区为高荧光区,组织切片中显示有大量的组织细胞积聚。CsA1mg组30d排异发生率为0/12,0.1mg组为5/8。ERG波幅的下降与CsA剂量和注射次数呈正相关。结论 异种RPE视网膜下腔移植在无免疫抑制剂的条件下,只能短期存活。CsA玻璃体腔中注射能抑制异种RPE移植的排异反应但易引起明显的视网膜毒性反应。     

Transferrin–Ricin A Chain Toxin Limits the Development of Experimental Proliferative Vitreoretinopathy

This study was designed to determine the safety and efficacy of transferrin–ricin A chain toxin (Tfr-rRA) at preventing retinal detachment in a rabbit model of proliferative vitreoretinopathy (PVR). The toxicity of intravitreal Tfr-rRA (1000–5000ng) was determined by indirect ophthalmoscopy and electroretinography on days 1, 5, 8, 16, 26 and 48 post-injection, and by light and transmission electron microscopy conducted on eyes enucleated 48 days after drug exposure. PVR was created by injecting 25000 homologous fibroblasts into the vitreous cavity of eyes which had previously undergone a gas compression vitrectomy. Eyes then received intravitreal Tfr-rRA (2000ng) or vehicle. Animals were examined on days 1, 4, 7, 10, 14, 21 and 28 post-injection. Intravitreal injection of 1000 and 2000ng Tfr-rRA did not show ophthalmoscopic or electroretinographic toxicity. Injection of 5000ng Tfr-rRA showed mild retinal whitening, retinal arteriolar narrowing, and electroretinographic toxicity, but no morphologic damage, such as photoreceptor loss, nuclear layer vacuolation, or inflammatory cell infiltration, to the retina. Tfr-rRA (2000ng) injected intravitreally 3 days after fibroblast injection prevented traction retinal detachment in 90% of eyes compared to 22% of sham treated eyes (P< 0.001). The data from this study suggest that transferrin-ricin A chain toxin (2000ng) safely and effectively limits retinal detachment in experimental PVR.     

Preclinical investigation of fluorometholone acetate as a potential new adjuvant during vitreous surgery

Objective To examine the effects of intravitreal fluorometholone acetate (FMT) on the morphology and function of the retina and to investigate its possible use for vitreous surgery. Methods Brown Norway rat eyes (n = 6, 12 groups) were injected with 0.05 ml of SF₆ gas for vitrectomization. Four weeks later, FMT solution was injected into the vitreous cavity/subretinal space of the vitrectomized eyes at doses of 10, 20, and 40 mg/ml (0.05 ml/eye, n = 12 for each group). The retinal function was evaluated by electroretinography (ERG) at 4 and 8 weeks after FMT injection. Retinal toxicity was also assessed histologically by a light microscopy. Sham-operated eyes (0.05 ml of irrigating solution, n = 12) were used as control animals. FMT-assisted pars plana vitrectomy with internal limiting membrane (ILM) peeling was performed in primate eyes (n = 2). Retinal toxicity was assessed by ophthalmoscope, fluorescein angiography and electron microscopy three months after the vitreous surgery. Results There was no remarkable reduction in any ERG waves at either time interval at 4 and 8 weeks after the intravitreal/subretinal injection of FMT. No obvious histological change was observed in any of the rat eyes either. Using ophthalmoscope, fluorescein angiography and electron microscopy, the appearance of the primate retinas remained to be in a non-pathological condition. Conclusion FMT appears to be a potentially useful tool in assisting vitreous surgery including safe ILM peeling. The study was supported in part by grants from the Ministry of Education, Science, Sports and Culture, Japan (Grant-in-Aid for Scientific Research #17591839, #14571676).     

兔玻璃体内注射聚N-异丙基丙烯酰胺-聚氧化乙烯纳米粒的眼内毒理学效应

目的:评估玻璃体腔内注射新型缓释给药载体聚N-异丙基丙烯酰胺-聚氧化乙烯(PNIPAAm-PEO)纳米粒的眼内毒理学效应。方法:玻璃体腔注射不同浓度(1mg/0.1mL,2mg/0.1mL,3mg/0.1mL,4mg/0.1mL)的PNIPAAm-PEO纳米稀释液后于不同时间点行裂隙灯、检眼镜、视网膜电图以及组织病理学检测。对照组注射0.1mL无菌生理盐水。将所用不同浓度稀释液局部点眼,观察局部组织的刺激反应。结果:兔眼角结膜对检测浓度范围内的PNIPAAm-PEO有良好耐受性,眼部无刺激症状。玻璃体腔内注射1mg和2mg组未见明显视网膜毒性反应。3mg组眼底检查无异常,ERG-b波1~3d下降幅度>30%,第7~14d略有恢复;第14d光镜下视网膜部分感光细胞外节间隙增宽,外丛状层以内结构空泡变性,细胞排列正常;电镜下各层均有较明显的结构改变,广泛的细胞水肿和空泡变性,细胞间隙增宽,感光细胞膜盘结构基本正常。4mg组ERG-b波波幅下降>30%;第1~14d组织病理学观察均有明显视网膜结构破坏,广泛空泡变性,部分感光细胞的盘膜崩解,层状结构紊乱、模糊不清。结论:PNIPAAm-PEO纳米粒的眼部耐受性良好,具有用作眼部给药载体的潜力,但大剂量使用时应注意眼部安全性问题。