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(Investigative Ophthalmology and Visual Science. 2003;44:4989-4993.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0600
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Periocular Injection of Microspheres Containing PKC412 Inhibits Choroidal Neovascularization in a Porcine Model

Yoshitsugu Saishin,1,2 Raquel Lima Silva,1,2 Yumiko Saishin,1,2 Kevin Callahan,1,2 Christian Schoch,3 Markus Ahlheim,3 Hong Lai,1 Frances Kane,4 R. K. Brazzell,4 David Bodmer,3 and Peter A. Campochiaro1,2

1From the Departments of Ophthalmology and 2Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland; 3Pharmaceutical and Analytical Development, Novartis Pharma AG, Basel, Switzerland; and 4Novartis Ophthalmics, Duluth, Georgia.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. Oral administration of PKC412, a kinase inhibitor that blocks several isoforms of protein kinase C (PKC) and receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor, and stem cell factor, inhibits ocular neovascularization in a murine model. The purpose of this study was to determine whether sustained local delivery of PKC412 in a human-sized eye inhibits choroidal neovascularization (CNV).

METHODS. Laser photocoagulation was used to rupture Bruch’s membrane in young domestic pigs, and then a periocular injection of control microspheres or microspheres containing 25% or 50% PKC412 was given. After 10 days the integrated area of CNV at Bruch’s membrane rupture sites was measured by image analysis. The levels of PKC412 in choroid, retina, and vitreous were measured either 10 or 20 days after periocular injection of 50% PKC microspheres or at 20 days after injection of 25% PKC412 microspheres.

RESULTS. The areas of CNV at Bruch’s membrane rupture sites were significantly smaller in eyes that received a periocular injection of microspheres containing 25% (P = 0.0042) or 50% (P = 0.0012) PKC412 than those in eyes injected with control microspheres. Ten days after periocular injection of 50% PKC412 microspheres, PKC412 was detected in the choroid, but not in the retina or vitreous. Twenty days after periocular injection of 50% PKC412, high levels of PKC412 were measured in the choroid, vitreous, and retina. Levels were lower but still substantial in all three compartments 20 days after periocular injection of 25% microspheres.

CONCLUSIONS. Sustained local delivery of PKC412 provides a promising approach for treatment of CNV.

Although multiple stimuli may be involved in the development of CNV, VEGF seems to play a particularly important role. Increased levels of VEGF have been demonstrated in RPE cells in association with CNV,1 2 3 4 and agents that block signaling through VEGF receptors5 or sequester VEGF6 7 suppress the development of CNV. These preclinical studies predict that antagonizing VEGF is a good approach for treatment of CNV, and preliminary results in clinical trials suggest that this prediction may be correct8 (Rosenfeld PJ, et al. IOVS 2003;44:ARVO E-Abstract 970).

Kinase inhibitors, such as PKC412, provide an efficient way to block signaling through VEGF receptors.5 9 10 Because PKC412 blocks both VEGF receptors 1 and 2, in addition to neutralizing the effects of VEGF, it also blocks the effects of other members of the VEGF family, such as placental growth factor, that may also play a role. Also, PKC412 is a small molecule, allowing it to be delivered by routes other than intravitreous injection, which carries risk of endophthalmitis and retinal detachment. A potential disadvantage is that the high homology among receptor tyrosine kinases makes it difficult to develop highly specific kinase inhibitors. In addition to blocking VEGF receptors, PKC412 blocks the receptors for PDGF and stem cell factor and inhibits several isoforms of PKC.9 There is always the possibility of unintended unfavorable consequences from one of these other activities. But it is also possible that these other activities are fortuitous, and in fact PDGFs have been implicated as contributors to proliferative retinopathies,11 12 PKCs contribute to vascular proliferation and leakage,13 14 and recently it has been shown that erythropoietic stem cells may contribute to neovascularization.15

In a phase 2 clinical trial, oral administration of PKC412 was found to decrease retinal thickening significantly in patients with macular edema due to diabetic retinopathy (Campochiaro PA, et al. IOVS 2003;44:ARVO E-Abstract 4286). However, some patients experienced nausea and vomiting, which generally was not serious, but still unpleasant. Also, a small number of patients showed elevation of liver enzymes, which required careful monitoring. These adverse effects could be avoided by sustained local delivery of PKC412. In this study, we investigated the effect of periocular injection of microspheres containing PKC412. We used a pig model of CNV, because the pig eye is similar to the human eye in size and thickness of the sclera.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
PKC412 and poly(d,l lactide-co-glycolide)glucose are produced by Novartis Pharma (Basel, Switzerland). Poly(vinylalcohol) (Mowiol 4-88) was purchased from Clariant (Frankfurt, Germany). An aqueous vehicle containing sodium carboxymethylcellulose, poloxamer 188 (Pluronic F68; BASF, Ludwigshafen, Germany) and mannitol was used for suspension of microspheres.

Manufacturing of PKC412 Microspheres: 25% and 50% Loading
A solution of PKC412 drug substance and poly(d,l lactide-co-glycolide) glucose in methylene chloride was emulsified with a 1.5% aqueous solution of poly(vinylalcohol) and fed into a stirred tank reactor containing 0.5% aqueous solution of poly(vinylalcohol). The resultant emulsion was heated to 42°C with stirring for 30 minutes and then cooled to room temperature. The microspheres were allowed to sediment, the aqueous supernatant was removed, and the microspheres were washed twice by suspending in water, heating to 42°C with stirring for 30 minutes, sedimenting, and pouring off the supernatant. The microspheres were collected with a 5-mm filter, dried in a vacuum, sieved with a 140-mm filter, and sterilized in bulk by gamma irradiation (30 ± 2 kGy).

Characterization of Microspheres
Microspheres were dissolved in acetonitrile-methanol, and the polymer fraction was precipitated with an aqueous buffer. The amount of PKC412 in the liquid phase was measured by a standard HPLC method. Particle size was determined by the amount of diffraction of a beam of laser light passed through an aqueous suspension of microspheres. Residual methylene chloride was determined by headspace gas chromatography of a heated solution of microspheres in dimethylformamide.

Rupture of Bruch’s Membrane and Periocular Injections in Pigs
Four-week-old female Yorkshire pigs were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research in a protocol approved by the Animal Care and Use Committee of the Johns Hopkins University School of Medicine. The pigs were given 1% to 4% halothane by mask inhalation and then intubated. Anesthesia was maintained by inhalation of 1% to 3% halothane, 2% O2, and 1% NO2. During anesthesia, heart rate and O2 saturation were monitored by pulse oximetry. Pupils were dilated with 1% tropicamide, and a fundus contact lens was placed on the cornea. The same approach was used to rupture Bruch’s membrane as that previously described in mice.16 In preliminary experiments, a portable diode laser with a slit lamp delivery system was used to rupture Bruch’s membrane in several locations, using a 75-mm spot size, 0.1-second duration, and several different power settings. As previously observed in mice, rupture of Bruch’s membrane was accompanied by formation of a vaporization bubble. With our laser, the lowest power that consistently caused rupture of Bruch’s membrane, as judged by the formation of a bubble, was 400 mW, and therefore this power setting was used. It should be noted that the lowest power setting that consistently causes rupture of Bruch’s membrane may vary with different lasers, and it is important to perform the titration described earlier. To investigate the effect of PKC-containing microspheres, Bruch’s membrane was ruptured in eight locations equidistant from and encircling the optic nerve in each eye of four pigs. After completion of the laser, two pigs received a periocular injection of 1.0 mL containing 100 mg of 25% PKC412 and two pigs received periocular injection of 1.0 mL containing 100 mg of 50% PKC412 in one eye. All four pigs received a periocular injection of 1.0 mL of placebo microspheres in the fellow eye. After 10 days, the pigs were killed and eyes were removed and frozen in optimal cutting temperature (OCT) compound (Tissue-Tek; Sakura Finetek, Torrance, CA).

Histopathologic Assessment of CNV
Frozen serial sections (10 µm) were cut through the entire extent of each burn and histochemically stained with Griffonia simplicifolia lectin B4 (GSA; Vector Laboratories, Burlingame, CA), which selectively stains vascular cells. A dye (HistoMark Red; Kirkegaard and Perry, Cabin John, MD) was used to stain the reaction product red, allowing it to be distinguished from melanin. Some slides were counterstained with hematoxylin (Sigma Diagnostics, St. Louis, MO). Sections were examined by microscope (Axioskop; Carl Zeiss Meditec, Inc., Thornwood, NY), and images were digitized with a three charge-coupled device (CCD) video camera (IK-TU40A; Toshiba, Tokyo, Japan) and frame grabber. Image-analysis software (Image-Pro Plus; Media Cybernetics, Silver Spring, MD) was used to delineate and measure the area of GSA-stained blood vessels in the subretinal space on each slide. Area measurements were made for all sections on which some of the lesion appeared and added together to give the integrated area of CNV at each Bruch’s membrane rupture site, as previously described.10 If even one section was of such poor quality that the area of CNV could not be measured, then that CNV lesion was discarded.

Measurement of Tissue and Plasma Levels of PKC412
PKC412 was measured by HPLC in tissues dissected from three porcine eyes: one, 10 days after periocular injection of 1.0 mL of 50% PKC412 microspheres; one, 20 days after periocular injection of 50% PKC412 microspheres; and one, 20 days after periocular injection of 1.0 mL of 25% PKC412 microspheres. After death, the eyes were rapidly removed and the vitreous, retina, and RPE-choroid were dissected and frozen. Plasma was also obtained and frozen.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
The characteristics of 25% and 50% PKC412 microspheres are listed in Table 1 . Periocular injection of microspheres alone (placebo) or microspheres containing 25% or 50% PKC412 caused mild conjunctival injection that was similar among the three groups. There were no discernible signs of inflammation or irritation. Ten days after rupture of Bruch’s membrane and periocular injection of the microspheres, pigs were examined just before (Figs. 1A 1C) or just after (Fig. 1B) death. The microspheres appeared as bulges beneath the conjunctiva. Gross pathologic examination of the eyes showed collections of microspheres on the outside of the sclera occupying approximately 1 quadrant of the eye extending from a few millimeters posterior to the limbus to the optic nerve (Figs. 1D 1E 1F) . All the eyes were similar in appearance, with no gross signs of inflammation.


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  		TABLE 1. Characterization of PKC412 Microspheres

 


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  		FIGURE 1. Periocular injection of microspheres containing PKC412 suppressed CNV. (A) Empty microspheres (placebo) were seen as bulges under the conjunctiva (arrows) 10 days after injection. There was a similar appearance 10 days after periocular injection of microspheres containing 25% (B) or 50% (C) PKC412. Gross pathologic examinations showed large collections of microspheres (arrows) that were similar in eyes injected with empty microspheres (D) or microspheres containing 25% (E) or 50% (F) PKC412. The microspheres often occupied an entire quadrant of the outside of an eye and extended back to the optic nerve (arrowheads). (G) Ten days after rupture of Bruch’s membrane and periocular injection of empty microspheres, a large area of CNV (arrows) was seen at a rupture site in Bruch’s membrane. (H) Ten days after rupture of Bruch’s membrane and injection of microspheres containing 25% PKC412, there was very little CNV (arrows) at a rupture site. (I) Ten days after rupture of Bruch’s membrane and injection of microspheres containing 50% PKC412, there was very little CNV (arrows) at a rupture site. (J) Another rupture site from an eye injected with empty microspheres shows a large area of CNV (arrows), whereas other rupture sites in eyes injected with microspheres containing 25% (K) or 50% (L) showed very little CNV (arrows).

 
There were large areas of CNV at Bruch’s membrane rupture sites in eyes that had received a periocular injection of placebo microspheres (Figs. 1G 1J) . In contrast, areas of CNV at rupture sites were noticeably smaller in eyes treated with microspheres containing 25% (Figs. 1H 1K) or 50% PKC412 (Fig. 1I 1L) . Measurement of the integrated area of CNV at Bruch’s membrane rupture sites by image analysis with the investigator masked with respect to treatment group, showed significantly smaller areas of CNV at rupture sites in eyes treated with 25% or 50% PKC412 microspheres, compared with eyes treated with placebo microspheres (Fig. 2) .



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  		FIGURE 2. Periocular injection of microspheres containing PKC412 significantly reduced the development of CNV at rupture sites in Bruch’s membrane. Measurement of the integrated area of CNV at Bruch’s membrane rupture sites by image analysis with the investigator masked to treatment group, showed significantly smaller areas of CNV at rupture sites in eyes treated with 25% or 50% PKC412 microspheres, compared with eyes treated with placebo microspheres. Statistical comparisons were made with a generalized linear mixed model with the Dunnett correction for multiple comparisons.

 
Ten days after periocular injection of 100 mg of microspheres containing 50% PKC412, levels of PKC412 were below the level of detection in the plasma, vitreous, and retina, but were measurable in the choroid (Table 2) . Twenty days after periocular injection of 100 mg of 50% PKC412 microspheres, there were high levels of PKC412 in choroid, vitreous, and retina. In an eye given a periocular injection of 100 mg of 25% PKC412 microspheres, the levels of PKC412 in each of the three compartment 20 days after the injection were much lower than those in the eye injected with 50% microspheres, but were still substantial. With either dose, there was no detectable PKC412 in plasma.


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  		TABLE 2. Ocular Levels of PKC412 after Periocular Injection of Microspheres Containing PKC412

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this study, we demonstrated that periocular injection of microspheres containing PKC412 caused significant suppression of the development of CNV at rupture sites in Bruch’s membrane in pigs. Ten days after injection of microspheres containing 50% PKC412, PKC412 was detectable in the choroid, but not the retina or vitreous. Twenty days after injection of microspheres containing 50% PKC412, levels were quite high in the choroid and lower, but still substantial, in the vitreous and retina. Twenty days after injection of 25% PKC412 microspheres, levels of PKC412 in choroid, vitreous, and retina were lower than those after injection of 50% PKC412 microspheres, but still well above the level of detection. This suggests that the microspheres were providing sustained delivery of PKC412, with levels increasing between 10 and 20 days after injection and were able to suppress the development of CNV. This provides proof of concept for local transscleral delivery of PKC412 for treatment of CNV.

Local delivery of antiangiogenic agents to the eye is an appealing approach for treatment of ocular neovascularization. One method to achieve this objective is to inject drugs into the vitreous cavity, an approach that is being tested in clinical trials for delivery of an aptamer that binds VEGF and an anti-VEGF antibody fragment8 (Rosenfeld PJ, et al. IOVS 2003;44:ARVO E-Abstract 970). With this approach, high drug levels can be achieved rapidly in both the retina and the choroid, but clearance is also quite rapid, requiring that injections be repeated every few weeks. This is inconvenient for the patient and the doctor, but more important, each injection carries some risk of endophthalmitis and retinal detachment. Whether the magnitude of this risk is acceptable or a serious drawback should be determined in ongoing clinical trials. Another approach is to implant a nonbiodegradable device into the vitreous cavity to slowly release drug over a prolonged period. This technique was successfully used to deliver ganciclovir for the treatment of CMV retinitis17 and is currently being tested for intraocular delivery of steroids for the treatment of macular edema.18 19 Although a surgical procedure is necessary to insert the device, it is possible to sustain delivery for years, depending on the drug, and therefore supplemental insertions or replacements are relatively infrequent. This may be acceptable for elderly patients who may require only a few procedures, but is not ideal for young patients. By using small biodegradable sustained-release formulations, it is possible to perform intravitreous injections in the clinic. This has the same advantages and disadvantages as the intravitreous injection of aptamers or antibody fragments, with the added advantage of sustained release, which could decrease the frequency of injections. This approach is currently being tested in a clinical trial of sustained delivery of dexamethasone for macular edema (Kuppermann BD, et al. IOVS 2003;44:ARVO E-Abstract 4289).

The risks of repeated intraocular injections or surgical procedures may be acceptable if these approaches have far superior efficacy to other modes of delivery. Transscleral delivery of agents does not require penetration of the eye and disruption of the vitreous and therefore is theoretically safer, but little is known about what sort of drug levels can be achieved in the various intraocular compartments. It has been suggested that transscleral delivery of drugs is not feasible, because the rapid blood flow in the choroid would simply carry drugs away. The present study demonstrates that this theoretical concern is not a major problem, because a lipophilic drug, PKC412, is able to penetrate the sclera, achieve high levels in the choroid, and significantly suppress CNV at Bruch’s membrane rupture sites. Recently, we have demonstrated that periocular injection of adenoviral vectors encoding pigment epithelium-derived factor (PEDF) or soluble VEGF receptor 1 (Flt-1), results in transduction of periocular cells and transscleral penetration of the proteins into the eye, resulting in suppression of CNV.20 21 Therefore, even proteins of 50 or 79 kDa can penetrate the sclera and achieve therapeutic levels in the choroid. These data suggest that transscleral delivery of agents, particularly with a sustained delivery strategy, is a viable approach for treatment of choroidal diseases. Currently, periocular injection of an angiostatic steroid is being tested in clinical trials as a treatment for neovascular age-related macular degeneration, and preliminary results suggest some benefit.22

Detectable levels of PKC412 were also obtained in the retina and vitreous 20 days after periocular injection of PKC412 microspheres, suggesting the possibility that transscleral delivery can also be considered for treatment of retinal neovascularization. This is not the case for PEDF and soluble Flt-1, which after periocular gene transfer do not penetrate into the retina in sufficient amounts to inhibit retinal neovascularization,20 21 but small molecules like PKC412 may be able to do so. Additional studies are needed to explore this possibility, thoroughly investigate the pharmacokinetics, and determine the duration of PKC412 levels in the eye after periocular injection of PKC412 microspheres.


   Footnotes
 
Supported by National Eye Institute Grants EY05951, EY12609, P30EY1765; Novartis Ophthalmics; a Lew R. Wasserman Merit Award from Research to Prevent Blindness (PAC); and Dr. and Mrs. William Lake. PAC is the George S. and Dolores Dore Eccles Professor of Ophthalmology and Neuroscience.

Submitted for publication June 13, 2003; revised July 15, 2003; accepted July 18, 2003.

Disclosure: Yo. Saishin, None; R. Lima Silva, None; Yu. Saishin, None; K. Callahan, None; C. Schoch, Novartis AG (E); M. Ahlheim, Novartis Pharma (E); H. Lai, None; F. Kane, Novartis Ophthalmics (E); R.K. Brazzell, Novartis Ophthalmics (E); D. Bodmer, Novartis Pharma (E); P.A. Campochiaro, Novartis Ophthalmics (C, F), Alcon (F), Johnson and Johnson (F)

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Peter A. Campochiaro, Maumenee 719, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9277; pcampo{at}jhmi.edu.


   References
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 Abstract
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 Discussion
 References
 

  1. Amin, R, Pulkin, JE, Frank, RN. (1994) Growth factor localization in choroidal neovascular membranes of age-related macular degeneration Invest Ophthalmol Vis Sci 35,3178-3188[Abstract/Free Full Text]
  2. Kvanta, A, Algvere, PV, Berglin, L, Seregard, S. (1996) Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor Invest Ophthalmol Vis Sci 37,1929-1934[Abstract/Free Full Text]
  3. Lopez, PF, Sippy, BD, Lambert, HM, Thach, AB, Hinton, DR. (1996) Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes Invest Ophthalmol Vis Sci 37,855-868[Abstract/Free Full Text]
  4. Yi, X, Ogata, N, Komada, M, et al (1997) Vascular endothelial growth factor expression in choroidal neovascularization in rats Lab Invest 235,313-319
  5. Kwak, N, Okamoto, N, Wood, JM, Campochiaro, PA. (2000) VEGF is an important stimulator in a model of choroidal neovascularization Invest Ophthalmol Vis Sci 41,3158-3164[Abstract/Free Full Text]
  6. Kryzstolik, MG, Afshari, MA, Adamis, AP, et al (2002) Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment Arch Ophthalmol 120,338-346[Abstract/Free Full Text]
  7. Saishin, Y, Saishin, Y, Takahashi, K, et al (2003) VEGF-TRAPR1R2 suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier J Cell Physiol 195,241-248[CrossRef][Medline][Order article via Infotrieve]
  8. . The EyeTech Study Group (2002) Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration Retina 22,143-152[CrossRef][Medline][Order article via Infotrieve]
  9. Fabbro, D, Ruetz, S, Bodis, S, et al (2000) PKC412-a protein kinase inhibitor with a broad therapeutic potential Anti-Cancer Drug Design 15,17-28[Medline][Order article via Infotrieve]
  10. Seo, M-S, Kwak, N, Ozaki, H, et al (1999) Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor Am J Pathol 154,1743-1753[Abstract/Free Full Text]
  11. Seo, M-S, Okamoto, N, Vinores, MA, et al (2000) Photoreceptor-specific expression of PDGF-B results in traction retinal detachment Am J Pathol 157,995-1005[Abstract/Free Full Text]
  12. Mori, K, Gehlbach, P, Ando, A, et al (2002) Retina-specific expression of PDGF-B versus PDGF-A: vascular versus nonvascular proliferative retinopathy Invest Ophthalmol Vis Sci 43,2001-2006[Abstract/Free Full Text]
  13. Danis, RP, Bingaman, DP, Jirousek, M, Yang, Y. (1998) Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY 333531 Invest Ophthalmol Vis Sci 39,171-179[Abstract/Free Full Text]
  14. Suzuma, K, Takahara, N, Suzuma, I, et al (2002) Characterization of protein kinase C beta isoform’s action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization Proc Natl Acad Sci USA 99,721-726[Abstract/Free Full Text]
  15. Grant, MB, May, WS, Caballero, S, et al (2002) Adult hematopoietic stem cells provide functional hemangioblastic activity during retinal neovascularization Nat Med 8,607-612[CrossRef][Medline][Order article via Infotrieve]
  16. Tobe, T, Ortega, S, Luna, L, et al (1998) Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model Am J Pathol 153,1641-1646[Abstract/Free Full Text]
  17. Musch, DC, Martin, DF, Gordon, JF, Davis, MD, Kuppermann, BD. (1997) Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. The Ganciclovir Impant Study Group N Engl J Med 337,83-90[Abstract/Free Full Text]
  18. Jaffe, GJ, Ben-Nun, J, Guo, H, Dunn, JP, Ashton, P. (2000) Fluocinolone acetonide sustained drug delivery device to treat severe uveitis Ophthalmology 107,2024-2033[CrossRef][Medline][Order article via Infotrieve]
  19. Jaffe, GJ, Yang, CH, Guo, H, Denny, JP, Ashton, P. (2000) Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device Invest Ophthalmol Vis Sci 41,3569-3575[Abstract/Free Full Text]
  20. Gehlbach, P, Demetriades, AM, Yamamoto, S, et al (2003) Periocular gene transfer of sFlt-1 suppresses ocular neovascularization and VEGF-induced breakdown of the blood-retinal barrier Hum Gene Ther 14,129-141[CrossRef][Medline][Order article via Infotrieve]
  21. Gehlbach, P, Demetriades, AM, Yamamoto, S, et al (2003) Periocular injection of an adenoviral vector encoding pigment epithelium-derived factor inhibits choroidal neovascularization Gene Ther 10,637-646[CrossRef][Medline][Order article via Infotrieve]
  22. D’Amico, DJ, Goldberg, MF, Hudson, H, et al (2003) Anecortave acetate as monotherapy for the treatment of subfoveal lesions in patients with exudative age-related macular degeneration (AMD): interim (month 6) analysis of clinical safety and efficacy Retina 23,14-23[CrossRef][Medline][Order article via Infotrieve]



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