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Laboratory Sciences |

Intravitreous Bevacizumab Injection:  An Experimental Study in New Zealand White Rabbits FREE

Rafael T. Cortez, MD; Gema Ramirez, MD; Lucienne Collet, MD; Pranjal Thakuria, MD; G. Paolo Giuliari, MD
[+] Author Affiliations

Author Affiliations: Centro de Cirugía Oftalmológica, Universidad Central de Venezuela, Caracas, Venezuela (Drs Cortez, Ramirez, and Collet); Departments of Ophthalmology, Duke University, Durham, North Carolina (Dr Thakuria); and Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (Dr Giuliari).


Arch Ophthalmol. 2010;128(7):884-887. doi:10.1001/archophthalmol.2010.139.
Text Size: A A A
Published online

Objectives  To determine the effects of intraocular pressure (IOP) and needle diameter on the amount of reflux after intravitreous bevacizumab injection.

Methods  Prospective randomized interventional study. Twelve New Zealand white rabbits weighing approximately 2.5 to 3.5 kg each were randomized 1:1 to group 1 or group 2. Bevacizumab stained with trypan blue was used for intravitreous injection. To lower the IOP, eyes in group 2 underwent anterior chamber paracentesis before intravitreous injection. Two eyes in each group were injected using 27-, 30-, or 32-gauge needles. If a subconjunctival bleb formed after intravitreous injection, its diameter was measured using a caliper.

Results  The median IOP in group 1 was 17.5 mm Hg. Eyes injected using 27-gauge and 30-gauge needles showed stained subconjunctival blebs with median sizes of 3 mm and 1.7 mm, respectively; eyes injected using 32-gauge needles showed no subconjunctival bleb formation. The median IOP in group 2 was 10.3 mm Hg. Eyes injected using 27-gauge needles showed stained subconjunctival blebs with a median size of 0.7 mm, and eyes injected using 30-gauge and 32-gauge needles showed no subconjunctival bleb formation.

Conclusion  Decreasing the IOP before intravitreous injection and using a smaller-gauge needle reduce the risk of drug reflux after intravitreous bevacizumab injection.

Clinical Relevance  Intravitreous injection is an increasingly common route of drug delivery to treat ocular diseases. Techniques that maximize bioavailability are examined in this study.

Figures in this Article

Vascular endothelial growth factor (VEGF) acts in different physiologic processes, such as bone growth, tissue maintenance, wound healing, vasodilatation, and survival of various neuronal cell types, including retinal neurons.15 It has an active role in trophic maintenance of capillaries in several organs. In the eye, development of the choriocapillaris is dependent on continuous trophic support via VEGF secreted by the retinal pigment epithelium.6,7 The production of VEGF is increased when these cell types are subjected to hypoxia.8 In recent years, a strong association has been found between VEGF and development of ocular neovascular diseases.911

Bevacizumab is a potent monoclonal antibody that blocks all VEGF isoforms. Bevacizumab was the first anti-VEGF therapy approved by the US Food and Drug Administration for the treatment of breast, lung, and colorectal cancer.12 After the success of preliminary investigations with ranibizumab (an agent similar to bevacizumab) in the treatment of age-related macular degeneration, researchers and clinicians were motivated to systemically and intravitreously use bevacizumab off label to treat age-related macular degeneration and other forms of choroidal neovascular membranes.1315

Because of the significant adverse effects associated with the use of systemic anti-VEGF medications, a trend to administer bevacizumab by intravitreous injection has been seen among vitreoretinal surgeons.16,17 Although some authors advocate the ocular safety of bevacizumab,1820 it may enter the systemic circulation after the intravitreous route.17,21,22 Nevertheless, intravitreous injections of this agent provide an effective route for retinal neovascular disease therapy. A drawback of this technique is the risk of associated complications such as endophthalmitis, retinal detachment, and cataract formation.23 Recently, attention has been paid to other complications such as temporary intraocular pressure (IOP) increase and reflux of medication, with subconjunctival bleb formation after intravitreous injection.2426 Several ophthalmologists have modified the intravitreous injection technique in an effort to decrease the incidence of this reflux; however, most researchers have not considered the role of IOP.27,28

The objectives of this study were to determine the effects of IOP and needle diameter on the amount of reflux after intravitreous bevacizumab injection. We also aimed to determine if bevacizumab is present in the subconjunctival bleb.

STUDY DESIGN

This was a prospective randomized interventional study with direct comparison of the reflux after intravitreous bevacizumab injection and the effects of IOP and needle diameter on the amount of reflux, measured by subconjunctival bleb formation. The ethical committee of the Centro de Cirugía Oftalmológica and Universidad Central de Venezuela, Caracas, approved the study. All experiments were performed in accord with the research association for the use of animals at the Universidad Central de Venezuela.

SUBJECT SELECTION AND RANDOMIZATION

Twelve New Zealand white rabbits weighing approximately 2.5 to 3.5 kg each were obtained from the Animal Research Department of the Universidad Central de Venezuela. Rabbits were chosen for this study because of their usefulness in the evaluation of new drugs and surgical procedures for glaucoma.29,30 They were randomized 1:1 to group 1 or group 2. Eyes in group 1 were considered the control group, as no attempt was made to lower the IOP. In group 2, anterior chamber paracentesis was performed to lower the IOP.31,32 Two eyes in each group were then randomized 1:1:1 to receive intravitreous bevacizumab injections using 27-, 30-, or 32-gauge needles.

TECHNIQUE AND TREATMENT

Rabbits in both groups were anesthetized by a certified anesthesiologist using intramuscular ketamine hydrochloride injection.33,34 Topical anesthesia with proparacaine hydrochloride, 0.5%, was administered to each study eye 1 to 5 minutes before intravitreous injection. The intravitreous injection solution consisted of a mixture of 0.8 mL of bevacizumab and 0.2 mL of trypan blue. Trypan blue was used to stain the bevacizumab and to determine its presence if a subconjunctival bleb formed. The intravitreous injection was prepared in the usual manner. The ocular surface and cul-de-sac were rinsed generously with a povidone-iodine solution, 5%, while the eyelids were scrubbed with a cotton-tipped applicator soaked in povidone-iodine solution, 10%. After placing a sterile eyelid speculum, povidone-iodine solution, 5%, was applied directly over the injection site. Using a 30-gauge needle, eyes in group B underwent anterior chamber paracentesis in a controlled manner under magnification before intravitreous injection.35 The volume extracted by anterior chamber paracentesis varied from approximately 100 to 200 μL. Intraocular pressure was then assessed (Tono-Pen XL; Medtronic Solan, Jacksonville, Florida) in eyes of both groups. All intravitreous injections were performed by one of us (R.T.C.) with retina training and experience using an oblique intravitreous injection technique delivered 1.5 to 2 mm posterior to the superotemporal limbus. Using a 27-, 30-, or 32-gauge needle, 0.025 mL of the previously described bevacizumab–trypan blue mixture was injected. As soon as the needle was withdrawn, the external area was observed for the presence of any subconjunctival bleb that stained blue. If present, the subconjunctival bleb was measured using a straight Castroviejo caliper (K3-9000; Katena Products, Inc, Denville, New Jersey).

STUDY END POINTS

The primary end point was to determine if the IOP had an effect on the amount of reflux after intravitreous bevacizumab. Secondary end points were to determine if the needle diameter had a role in subconjunctival bleb formation and whether the content of that subconjunctival bleb was composed of refluxed bevacizumab.

STATISTICAL ANALYSIS

The results obtained in group 1 and group 2 were compared. Statistical analysis was performed using unpaired t test and commercially available software (STATA 8; StataCorp LP, College Station, Texas).

Twelve eyes of 12 New Zealand white rabbits were included in the study. After randomization, 6 eyes were included in each group (group 1 and group 2). In group 2 eyes, the IOP was lowered by anterior chamber paracentesis using the aforedescribed technique. All study eyes were injected with the bevacizumab–trypan blue mixture. After the second randomization, 2 eyes in each group were injected using 27-, 30-, or 32-gauge needles.

GROUP 1

Eyes in group 1 had a median IOP of 17.5 mm Hg (range, 17-18 mm Hg). Eyes injected using 27-gauge needles showed trypan blue–stained subconjunctival blebs with a median size of 3 mm (range, 2.9-3.1 mm) (Figure, A). Eyes injected using 30-gauge needles showed trypan blue–stained subconjunctival blebs with a median size of 1.7 mm (range, 1.6-1.8 mm). Eyes injected using 32-gauge needles showed no subconjunctival bleb formation.

Place holder to copy figure label and caption
Figure.

Trypan blue–stained subconjunctival blebs secondary to reflux after intravitreous bevacizumab injection. A, Group 1 eye with a 3.1-mm subconjunctival bleb after intravitreous injection using a 27-gauge needle. B, Group 2 eye with a 0.7-mm subconjunctival bleb after intravitreous injection using a 27-gauge needle.

Graphic Jump Location
GROUP 2

To lower the IOP, eyes in group 2 underwent anterior chamber paracentesis before intravitreous injection. After this procedure, eyes in group 2 had a median IOP of 10.3 mm Hg (range, 10-11 mm Hg). Eyes injected using 27-gauge needles showed trypan blue–stained subconjunctival blebs with a median size of 0.7 mm. Eyes injected using 30- or 32-gauge needles showed no subconjunctival bleb formation (Figure, B).

STATISTICAL ANALYSIS

Comparing the effects of 32-gauge vs 30-gauge and 27-gauge needles in group 1, the median size of subconjunctival blebs differed significantly (P = .003 and P = .001, respectively). Comparing the effects of 27-gauge vs 30-gauge needles in group 1, the median size of subconjunctival blebs also differed significantly (P = .01).

The effects of 32-gauge and 30-gauge vs 27-gauge needles were compared in group 2. The median size of subconjunctival blebs differed significantly (P < .001).

Comparing the effects of 27-gauge needles in group 1 vs group 2, the median size of subconjunctival blebs differed significantly (P = .002). Comparing the effects of 30-gauge needles in group 1 vs group 2, the median size of subconjunctival blebs also differed significantly (P = .003).

In 1911, Ohm36 introduced the use of intravitreous injections of air to repair retinal detachment. In the 1940s, penicillin was used to treat endophthalmitis.37 Today, intravitreous drug injections provide an effective route for retinal disease therapy. Since the advent of anti-VEGF therapies, use of the intravitreous injection technique has steadily increased. However, concern has been expressed about potential unwanted secondary systemic absorption of these drugs.16,17 The effects may lead to serious complications such as systemic hypertension, thromboembolic diseases, and death.38,39

A 2007 study40 evaluated short-term IOP after intravitreous bevacizumab injection. The authors reported IOP elevation 30 minutes after intravitreous injection in a few patients. These results have been confirmed by others in 2 studies.41,42 In one study,41 some patients required eyedrops to lower the IOP; however, no patients needed anterior chamber paracentesis. In the other study,42 IOP of less than 30 mm Hg was seen 15 minutes after intravitreous injection in all patients, also without need for anterior chamber paracentesis. Nevertheless, a point of concern is that reflux may occur after intravitreous bevacizumab injection following removal of the needle, causing a subconjunctival bleb that may contain some of the injected drug,26 which might affect drug bioavailability and absorption. To minimize the amount of vitreous reflux, a modified technique using a tunneled scleral incision has been suggested.28 Anterior chamber paracentesis before intravitreous injection may prevent reflux, ensuring that the complete dose of the agent used remains in the vitreous cavity; however, anterior chamber paracentesis per se carries the risks of infection and lens damage.32

While injecting intravitreous bevacizumab in our practice, we observed that the drug inside the eye has an oily appearance. It adheres to the tip of the needle and is “pulled” to the vitreous base when withdrawing the needle (video; http://www.archophthalmol.com).

Herein, we considered not only the effects of needle diameter and an oblique injection technique as suggested by previous authors27,28 but also the possible key role of IOP in reflux after intravitreous injection. Our results showed that decreasing the IOP before intravitreous injection and using a smaller-gauge needle reduce the amount of drug reflux after intravitreous bevacizumab injection.

In conclusion, we observed in our cohort of eyes that subconjunctival blebs formed after intravitreous injection contain bevacizumab instead of fluid vitreous humor alone. In addition, the size of subconjunctival blebs is in direct proportion to the IOP and the needle diameter. Limitations of our study include our small sample size, as well as reported IOP measurement variation in New Zealand white rabbits.43 Until larger prospective randomized interventional studies are performed, we recommend decreasing the IOP before intravitreous bevacizumab injection and using a 32-gauge needle and an oblique injection technique. This technique includes placement of a cotton swab at the injection point immediately after removal of the needle in an effort to avoid reflux of bevacizumab, which may enter the systemic circulation. Intraocular pressure can be reduced by anterior chamber paracentesis.32 However, in our practice we prefer to place a mercury bag over the eye for 20 to 30 minutes before intravitreous injection. This is effective and avoids the risks associated with anterior chamber paracentesis.

Correspondence: G. Paolo Giuliari, MD, Princess Margaret Hospital, University of Toronto, 77 Elm St, Apt 903, Toronto, ON M5G 1H4, Canada (gpgiuliari@gmail.com).

Submitted for Publication: October 12, 2009; final revision received December 20, 2009; accepted January 7, 2010.

Financial Disclosure: None reported.

Additional Contributions: The Animal Research Department of the Universidad Central de Venezuela assisted with this study.

Gerber  HPVu  THRyan  AMKowalski  JWerb  ZFerrara  N VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999;5 (6) 623- 628
PubMed Link to Article
Eremina  VSood  MHaigh  J  et al.  Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111 (5) 707- 716
PubMed Link to Article
Nissen  NNPolverini  PJKoch  AEVolin  MVGamelli  RLDiPietro  LA Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol 1998;152 (6) 1445- 1452
PubMed
Arsic  NZacchigna  SZentilin  L  et al.  Vascular endothelial growth factor stimulates skeletal muscle regeneration in vivo. Mol Ther 2004;10 (5) 844- 854
PubMed Link to Article
LeCouter  JMoritz  DRLi  B  et al.  Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003;299 (5608) 890- 893
PubMed Link to Article
Nishijima  KNg  YSZhong  L  et al.  Vascular endothelial growth factor–A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 2007;171 (1) 53- 67
PubMed Link to Article
Marneros  AGFan  JYokoyama  Y  et al.  Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 2005;167 (5) 1451- 1459
PubMed Link to Article
Shima  DTAdamis  APFerrara  N  et al.  Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1995;1 (2) 182- 193
PubMed
Caldwell  RBBartoli  MBehzadian  MA  et al.  Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev 2003;19 (6) 442- 455
PubMed Link to Article
Simó  RHernández  C Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy. Diabetologia 2008;51 (9) 1574- 1580
PubMed Link to Article
Miller  JWAdamis  APShima  DT  et al.  Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 1994;145 (3) 574- 584
PubMed
Yang  JCHaworth  LSherry  RM  et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349 (5) 427- 434
PubMed Link to Article
Michels  SRosenfeld  PJPuliafito  CAMarcus  ENVenkatraman  AS Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112 (6) 1035- 1047
PubMed Link to Article
Avery  RLPieramici  DJRabena  MDCastellarin  AANasir  MAGiust  MJ Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113 (3) 363- 372, e5
PubMed Link to Article
Yamamoto  IRogers  AHReichel  EYates  PADuker  JS Intravitreal bevacizumab (Avastin) as treatment for subfoveal choroidal neovascularization secondary to pathologic myopia. Br J Ophthalmol 2007;91 (2) 157- 160
PubMed Link to Article
Schachat  AP New treatments for age-related macular degeneration. Ophthalmology 2005;112 (4) 531- 532
PubMed Link to Article
van Wijngaarden  PCoster  DJWilliams  KA Inhibitors of ocular neovascularization: promises and potential problems. JAMA 2005;293 (12) 1509- 1513
PubMed Link to Article
Manzano  RPPeyman  GAKhan  PKivilcim  M Testing intravitreal toxicity of bevacizumab (Avastin). Retina 2006;26 (3) 257- 261
PubMed Link to Article
Shahar  JAvery  RLHeilweil  G  et al.  Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin) Retina 2006;26 (3) 262- 269
PubMed Link to Article
Maturi  RKBleau  LAWilson  DL Electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina 2006;26 (3) 270- 274
PubMed Link to Article
Drolet  DWNelson  JTucker  CE  et al.  Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharm Res 2000;17 (12) 1503- 1510
PubMed Link to Article
Gaudreault  JFei  DRusit  JSuboc  PShiu  V Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci 2005;46 (2) 726- 733
PubMed Link to Article
Gragoudas  ESAdamis  APCunningham  ET  JrFeinsod  MGuyer  DRVEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group, Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351 (27) 2805- 2816
PubMed Link to Article
Benz  MSAlbini  TAHolz  ER  et al.  Short-term course of intraocular pressure after intravitreal injection of triamcinolone acetonide. Ophthalmology 2006;113 (7) 1174- 1178
PubMed Link to Article
Morlet  NYoung  SH Prevention of intraocular pressure rise following intravitreal injection. Br J Ophthalmol 1993;77 (9) 572- 573
PubMed Link to Article
Boon  CJCrama  NKlevering  BJvan Kuijk  FJHoyng  CB Reflux after intravitreal injection of bevacizumab. Ophthalmology 2008;115 (7) 1270
PubMed Link to Article
Rodrigues  EBMeyer  CHGrumann  A  JrShiroma  HAguni  JSFarah  ME Tunneled scleral incision to prevent vitreal reflux after intravitreal injection. Am J Ophthalmol 2007;143 (6) 1035- 1037
PubMed Link to Article
Aiello  LPBrucker  AJChang  S  et al.  Evolving guidelines for intravitreous injections. Retina 2004;24 (5) ((suppl)) S3- S19
PubMed Link to Article
Abrams  LSVitale  SJampel  H Comparison of three tonometers for measuring intraocular pressure in rabbits. Invest Ophthalmol Vis Sci 1996;37 (5) 940- 944
PubMed
Katz  RSHenkind  PWeitzman  ED The circadian rhythm of the intraocular pressure in the New Zealand White rabbit. Invest Ophthalmol Vis Sci 1975;14775- 780
Pong  JC Anterior chamber paracentesis in patients with acute elevation of intraocular pressure. Graefes Arch Clin Exp Ophthalmol 2008;246 (3) 463- 466
PubMed Link to Article
Tsui  YPChiang  CCTsai  YY Paracentesis before intravitreal injection of bevacizumab. Can J Ophthalmol 2008;43 (2) 239- 240
PubMed Link to Article
Liu  DShao  YLuan  XZhang  MShui  CWu  Q Comparison of ketamine-pentobarbital anesthesia and fentanyl-pentobarbital anesthesia for open-heart surgery in minipigs. Lab Anim (NY) 2009;38 (7) 234- 240
PubMed Link to Article
Bimonte Patetta  DRodríguez Nieves  CCasas  LVedovatti Manzoni  E General anesthesia in rabbit [in Spanish]. Rev Eléctrón Vet. 2007;8 (6) 1695- 7504http://www.veterinaria.org/revistas/redvet/n070707/070719.pdf. Accessed April 19, 2010
Kane  ABarza  MBaum  J Intravitreal injection of gentamicin in rabbits: effect of inflammation and pigmentation on half-life ocular distribution. Invest Ophthalmol Vis Sci 1981;20 (5) 593- 597
PubMed
Ohm  J Uber die Behandlung der Netzhautablosung durch operative Entleerung der subretinalen Flossigkeit und Einspritzung von Luft in den Glaskorper [About the treatment of retinal detachment by surgical removal of the subretinal fluid and injection of air into the vitreous]. Graefes Arch Ophthalmol 1911;79442- 450
Link to Article
Rycroft  BW Penicillin and the control of deep intraocular infection. Br J Ophthalmol 1945;29 (2) 57- 87
PubMed Link to Article
Hurwitz  HFehrenbacher  LNovotny  W  et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350 (23) 2335- 2342
PubMed Link to Article
Sane  DCAnton  LBrosnihan  KB Angiogenic growth factors and hypertension. Angiogenesis 2004;7 (3) 193- 201
PubMed Link to Article
Hollands  HWong  JBruen  RCampbell  RJSharma  SGale  J Short-term intraocular pressure changes after intravitreal injection of bevacizumab. Can J Ophthalmol 2007;42 (6) 807- 811
PubMed Link to Article
Bakri  SJPulido  JSMcCannel  CAHodge  DODiehl  NHillemeier  J Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. Eye (Lond) 2009;23 (1) 181- 185
PubMed Link to Article
Falkenstein  IACheng  LFreeman  WR Changes of intraocular pressure after intravitreal injection of bevacizumab (Avastin). Retina 2007;27 (8) 1044- 1047
PubMed Link to Article
Lim  KSWickremasinghe  SSCordeiro  MFBunce  CKhaw  PT Accuracy of intraocular pressure measurements in New Zealand white rabbits. Invest Ophthalmol Vis Sci 2005;46 (7) 2419- 2423
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Trypan blue–stained subconjunctival blebs secondary to reflux after intravitreous bevacizumab injection. A, Group 1 eye with a 3.1-mm subconjunctival bleb after intravitreous injection using a 27-gauge needle. B, Group 2 eye with a 0.7-mm subconjunctival bleb after intravitreous injection using a 27-gauge needle.

Graphic Jump Location

Tables

References

Gerber  HPVu  THRyan  AMKowalski  JWerb  ZFerrara  N VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999;5 (6) 623- 628
PubMed Link to Article
Eremina  VSood  MHaigh  J  et al.  Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111 (5) 707- 716
PubMed Link to Article
Nissen  NNPolverini  PJKoch  AEVolin  MVGamelli  RLDiPietro  LA Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol 1998;152 (6) 1445- 1452
PubMed
Arsic  NZacchigna  SZentilin  L  et al.  Vascular endothelial growth factor stimulates skeletal muscle regeneration in vivo. Mol Ther 2004;10 (5) 844- 854
PubMed Link to Article
LeCouter  JMoritz  DRLi  B  et al.  Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003;299 (5608) 890- 893
PubMed Link to Article
Nishijima  KNg  YSZhong  L  et al.  Vascular endothelial growth factor–A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 2007;171 (1) 53- 67
PubMed Link to Article
Marneros  AGFan  JYokoyama  Y  et al.  Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 2005;167 (5) 1451- 1459
PubMed Link to Article
Shima  DTAdamis  APFerrara  N  et al.  Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1995;1 (2) 182- 193
PubMed
Caldwell  RBBartoli  MBehzadian  MA  et al.  Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev 2003;19 (6) 442- 455
PubMed Link to Article
Simó  RHernández  C Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy. Diabetologia 2008;51 (9) 1574- 1580
PubMed Link to Article
Miller  JWAdamis  APShima  DT  et al.  Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 1994;145 (3) 574- 584
PubMed
Yang  JCHaworth  LSherry  RM  et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349 (5) 427- 434
PubMed Link to Article
Michels  SRosenfeld  PJPuliafito  CAMarcus  ENVenkatraman  AS Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112 (6) 1035- 1047
PubMed Link to Article
Avery  RLPieramici  DJRabena  MDCastellarin  AANasir  MAGiust  MJ Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113 (3) 363- 372, e5
PubMed Link to Article
Yamamoto  IRogers  AHReichel  EYates  PADuker  JS Intravitreal bevacizumab (Avastin) as treatment for subfoveal choroidal neovascularization secondary to pathologic myopia. Br J Ophthalmol 2007;91 (2) 157- 160
PubMed Link to Article
Schachat  AP New treatments for age-related macular degeneration. Ophthalmology 2005;112 (4) 531- 532
PubMed Link to Article
van Wijngaarden  PCoster  DJWilliams  KA Inhibitors of ocular neovascularization: promises and potential problems. JAMA 2005;293 (12) 1509- 1513
PubMed Link to Article
Manzano  RPPeyman  GAKhan  PKivilcim  M Testing intravitreal toxicity of bevacizumab (Avastin). Retina 2006;26 (3) 257- 261
PubMed Link to Article
Shahar  JAvery  RLHeilweil  G  et al.  Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin) Retina 2006;26 (3) 262- 269
PubMed Link to Article
Maturi  RKBleau  LAWilson  DL Electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina 2006;26 (3) 270- 274
PubMed Link to Article
Drolet  DWNelson  JTucker  CE  et al.  Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharm Res 2000;17 (12) 1503- 1510
PubMed Link to Article
Gaudreault  JFei  DRusit  JSuboc  PShiu  V Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci 2005;46 (2) 726- 733
PubMed Link to Article
Gragoudas  ESAdamis  APCunningham  ET  JrFeinsod  MGuyer  DRVEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group, Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351 (27) 2805- 2816
PubMed Link to Article
Benz  MSAlbini  TAHolz  ER  et al.  Short-term course of intraocular pressure after intravitreal injection of triamcinolone acetonide. Ophthalmology 2006;113 (7) 1174- 1178
PubMed Link to Article
Morlet  NYoung  SH Prevention of intraocular pressure rise following intravitreal injection. Br J Ophthalmol 1993;77 (9) 572- 573
PubMed Link to Article
Boon  CJCrama  NKlevering  BJvan Kuijk  FJHoyng  CB Reflux after intravitreal injection of bevacizumab. Ophthalmology 2008;115 (7) 1270
PubMed Link to Article
Rodrigues  EBMeyer  CHGrumann  A  JrShiroma  HAguni  JSFarah  ME Tunneled scleral incision to prevent vitreal reflux after intravitreal injection. Am J Ophthalmol 2007;143 (6) 1035- 1037
PubMed Link to Article
Aiello  LPBrucker  AJChang  S  et al.  Evolving guidelines for intravitreous injections. Retina 2004;24 (5) ((suppl)) S3- S19
PubMed Link to Article
Abrams  LSVitale  SJampel  H Comparison of three tonometers for measuring intraocular pressure in rabbits. Invest Ophthalmol Vis Sci 1996;37 (5) 940- 944
PubMed
Katz  RSHenkind  PWeitzman  ED The circadian rhythm of the intraocular pressure in the New Zealand White rabbit. Invest Ophthalmol Vis Sci 1975;14775- 780
Pong  JC Anterior chamber paracentesis in patients with acute elevation of intraocular pressure. Graefes Arch Clin Exp Ophthalmol 2008;246 (3) 463- 466
PubMed Link to Article
Tsui  YPChiang  CCTsai  YY Paracentesis before intravitreal injection of bevacizumab. Can J Ophthalmol 2008;43 (2) 239- 240
PubMed Link to Article
Liu  DShao  YLuan  XZhang  MShui  CWu  Q Comparison of ketamine-pentobarbital anesthesia and fentanyl-pentobarbital anesthesia for open-heart surgery in minipigs. Lab Anim (NY) 2009;38 (7) 234- 240
PubMed Link to Article
Bimonte Patetta  DRodríguez Nieves  CCasas  LVedovatti Manzoni  E General anesthesia in rabbit [in Spanish]. Rev Eléctrón Vet. 2007;8 (6) 1695- 7504http://www.veterinaria.org/revistas/redvet/n070707/070719.pdf. Accessed April 19, 2010
Kane  ABarza  MBaum  J Intravitreal injection of gentamicin in rabbits: effect of inflammation and pigmentation on half-life ocular distribution. Invest Ophthalmol Vis Sci 1981;20 (5) 593- 597
PubMed
Ohm  J Uber die Behandlung der Netzhautablosung durch operative Entleerung der subretinalen Flossigkeit und Einspritzung von Luft in den Glaskorper [About the treatment of retinal detachment by surgical removal of the subretinal fluid and injection of air into the vitreous]. Graefes Arch Ophthalmol 1911;79442- 450
Link to Article
Rycroft  BW Penicillin and the control of deep intraocular infection. Br J Ophthalmol 1945;29 (2) 57- 87
PubMed Link to Article
Hurwitz  HFehrenbacher  LNovotny  W  et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350 (23) 2335- 2342
PubMed Link to Article
Sane  DCAnton  LBrosnihan  KB Angiogenic growth factors and hypertension. Angiogenesis 2004;7 (3) 193- 201
PubMed Link to Article
Hollands  HWong  JBruen  RCampbell  RJSharma  SGale  J Short-term intraocular pressure changes after intravitreal injection of bevacizumab. Can J Ophthalmol 2007;42 (6) 807- 811
PubMed Link to Article
Bakri  SJPulido  JSMcCannel  CAHodge  DODiehl  NHillemeier  J Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. Eye (Lond) 2009;23 (1) 181- 185
PubMed Link to Article
Falkenstein  IACheng  LFreeman  WR Changes of intraocular pressure after intravitreal injection of bevacizumab (Avastin). Retina 2007;27 (8) 1044- 1047
PubMed Link to Article
Lim  KSWickremasinghe  SSCordeiro  MFBunce  CKhaw  PT Accuracy of intraocular pressure measurements in New Zealand white rabbits. Invest Ophthalmol Vis Sci 2005;46 (7) 2419- 2423
PubMed Link to Article

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