Original Paper Received: January 13, 2014 Accepted: January 13, 2014 Published online: February 20, 2014
Pharmacology 2014;93:108–112 DOI: 10.1159/000358600
Topical Bevacizumab for Neovascular Glaucoma: A Pilot Study Michael Waisbourd a Gabi Shemesh a Shimon Kurtz a Rony Rachmiel a Elad Moisseiev a Shiri Zayit-Soudri a Anat Loewenstein a Irina Barequet b
a
Department of Ophthalmology, Tel Aviv Medical Center (affiliated to the Sackler Faculty of Medicine, Tel Aviv University), Tel Aviv, and b Goldschleger Eye Institute, Sheba Medical Center (affiliated to the Sackler Faculty of Medicine, Tel Aviv University), Tel Hashomer, Israel
Abstract Background/Aims: Bevacizumab (Avastin), an anti-vascular endothelial growth factor drug, has been successfully used in recent years to treat ocular pathologies, mostly by intravitreal administration. The aim of this study was to investigate the safety and efficacy of topically applied bevacizumab for the treatment of neovascular glaucoma (NVG). Methods: Patients with NVG were treated with topical bevacizumab (25 mg/ml) 4 times daily during 2 weeks. The following parameters were evaluated at baseline and on days 3, 7 and 14: visual acuity, slit-lamp examination, intraocular pressure (IOP), heart rate and systemic blood pressure. Iris neovascularization was documented using slitlamp color photos at baseline and on day 14. Results: Eight eyes of 8 patients with NVG were evaluated. After the 2-week treatment, mean IOP was lowered from 34.9 mm Hg (SD 12.8) at baseline to 28.8 mm Hg (SD 9.9) on day 14, representing a mean reduction of 6.1 mm Hg (17.5%). Three patients had clinical regression of their iris neovascularization. Ocular adverse events were transient and included mild upper eyelid swelling, mild exacerbation of superficial punctate keratitis and mild corneal epithelial bullae in an already edema-
© 2014 S. Karger AG, Basel 0031–7012/14/0934–0108$39.50/0 E-Mail [email protected] www.karger.com/pha
tous cornea. There were no serious systemic adverse events. Conclusions: Topical application of bevacizumab may lower IOP and result in regression of neovascularization in patients with NVG. © 2014 S. Karger AG, Basel
Introduction
Vascular endothelial growth factor (VEGF) is known to be a key player in the pathogenesis of neovascular glaucoma (NVG) [1], and intravitreal administration of the anti-VEGF drug bevacizumab (Avastin, Genentech, San Francisco, Calif., USA) has become a widely used treatment for patients with NVG, mostly in conjunction with or after completing panretinal photocoagulation. Intravitreal bevacizumab has been reported to result in regression of neovascularization of the iris and neovascularization of the angle and, consequently, reduction of intraocular pressure (IOP) [2–7]. Other studies showed that VEGF levels were significantly increased in the aqueous humor of patients with NVG [1], and subconjunctival injections of bevacizumab resulted in a decreased aqueous concentration of VEGF [8]. Furthermore, several animal studies showed that topically applied bevacizumab could reach detectable levels in the anterior chamber of the rabbit eye [9, 10]. This led us to hypothesize that topically Michael Waisbourd, MD Department of Ophthalmology, Tel Aviv Medical Center 6 Weizman Street Tel Aviv 64239 (Israel) E-Mail mwaisbourd @ hotmail.com
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Key Words Topical bevacizumab · Neovascular glaucoma · Anti-vascular endothelial growth factor
Table 1. Topical bevacizumab used in treating NVG: patients’ demographics and clinical parameters Patient Age, Sex Diagnosis No. years
Number of previous IVB injections (months prior to study1)
PRP treatment VA at VA at IOP at IOP at NV Adverse events (months prior to baseline day 14 baseline, day 14, regression study) mm Hg mm Hg
1 2 3 4
59 60 89 80
M M M F
CRVO, PXF OIS CRVO long-standing RD
2 (6) none 1 (11) none
complete (12) complete (4) complete (11) NA
20/400 LP NLP NLP
20/400 HM NLP NLP
21 38 47 48
16 28 36 36
– + + +
5 6 7 8
79 79 76 51
M F M M
long-standing RD CRAO failed TRD surgery PDR, TRD
3 (2) 2 (14) none none
NA complete (11) complete (8) complete (30)
NLP NLP HM NLP
NLP NLP HM NLP
42 46 12 25
43 36 15 20
– – – –
corneal epithelial bullae eyelid swelling mild SPK
IVB = Intravitreal bevacizumab; PRP = panretinal photocoagulation; VA = visual acuity; CRVO = central retinal vein occlusion; NV = neovascularization; M = male; F = female; PXF = pseudoexfoliation; OIS = ocular ischemic syndrome; LP = light perception; HM = hand movement; NLP = no light perception; RD = retinal detachment; CRAO = central retinal artery occlusion; TRD = tractional retinal detachment; SPK = superficial punctate keratitis; PDR = proliferative diabetic retinopathy; NA = not applicable, as it was impossible to perform panretinal photocoagulation in these patients. 1 Number of months since last intravitreal bevacizumab injection given prior to the study.
Materials and Methods
followed during this research. The study and data accumulation were carried out with approval from the Tel Aviv Medical Center Institutional Review Board. Informed consent for the research was obtained from each patient.
Results
Patients diagnosed with NVG secondary to various ocular pathologies were enrolled in the current study. Each subject’s past medical and ocular histories were reviewed and recorded. The study patients underwent baseline ophthalmic evaluation including best corrected visual acuity, slit-lamp examination of the anterior segment, corneal fluorescein staining for the evaluation of epithelial congruity, IOP measurements by Goldmann applanation tonometry and assessment of heart rate and systemic blood pressure levels. Each patient was then provided with a sterile bottle containing bevacizumab (75 mg/3 ml), which was prepared in the hospital’s pharmacy under sterile conditions. The patients were instructed to instill one drop (approximately 1.25 mg/0.05 ml bevacizumab per drop, equivalent to a concentration of 25 mg/ml) 4 times daily for 2 weeks into the affected eye. They were also taught to maintain strict punctal occlusion for at least 1 min after eyedrop instillation in order to reduce systemic drug absorption. Patients who were using other ocular drops were instructed to instill the bevacizumab drops first and then wait at least 5 min before instilling the other drops in order to prevent drug washout. Follow-up examinations were performed on days 3, 7 and 14 and included the same tests as those of the baseline examination. Slit-lamp color photography was performed at the baseline and final visits to document the extent of iris neovascularization. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were
Eight patients with NVG were enrolled. Table 1 details the patients’ demographics and clinical parameters. Six males and 2 females (mean age 71.6 years, range 51–89) received bevacizumab drops 4 times daily for a 2-week period. Patients’ glaucoma medications and other ocular topical treatments (e.g. artificial tears) remained unchanged during the study period. Visual acuity remained unchanged in 7 patients and was slightly improved in 1 patient (from light perception to hand motion detection). Overall, IOP decreased from a mean of 34.9 mm Hg (SD 12.8) at baseline to 28.8 mm Hg (SD 9.9) on day 14, representing a mean reduction of 6.1 mm Hg (17.5%). Figure 1 illustrates IOP curves for each patient, showing the value of IOP measured by applanation at each visit. Clinical regression of iris neovascularization was noted in 3 patients during the 14 days of follow-up, whereas in the other 5 patients, no substantial change in the extent of the anterior segment neovascularization was noted. Figure 2 presents color iris photographs showing partial regression of iris neovascularization and marked improvement of conjunctival injection over the 2-week follow-up in 2 patients.
Topical Bevacizumab for NVG
Pharmacology 2014;93:108–112 DOI: 10.1159/000358600
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applied bevacizumab may reduce the levels of VEGF in the anterior chamber and result in local regression of pathological neovascularization with subsequent lowering of IOP in patients with NVG.
50 Patient 1 Patient 2
IOP (mm Hg)
40
Patient 3
Color version available online
60
Patient 4
30
Patient 5 Patient 6
20
Patient 7 Patient 8
10
Fig. 1. IOP curves of 8 patients with NVG
who received topical bevacizumab (25 mg/ ml) for 2 weeks. Visit 1: baseline; visit 2: day 3; visit 3: day 7; visit 4: day 14.
Visit 1
Visit 2
Visit 3
Visit 4
Fig. 2. The effect of topical bevacizumab (25 mg/ml) in patients with NVG after 2 weeks. a–d Patient 1: iris neovascularization partially regressed and IOP fell from 38 to 28 mm Hg. e, f Patient 2: marked improvement of conjunctival congestion and lowering of IOP from 47 to 36 mm Hg.
a
b
c
d
e
f
No serious systemic adverse events were recorded during the study. The mean heart rate and systemic blood pressure measurements obtained from the entire study group remained stable during the study; they changed from 67.4 to 65.7 beats/min and from 153/76 to 148/75 110
Pharmacology 2014;93:108–112 DOI: 10.1159/000358600
mm Hg, respectively. Few ocular adverse events were noted during the study. One patient had a mild upper eyelid swelling; 1 patient had mild exacerbation of superficial punctate keratitis, and mild corneal epithelial bullae were noted in one eye of a patient with preexisting corneal edeWaisbourd et al.
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Color version available online
0
Discussion
The results of this pilot study suggest that short-term use of topical bevacizumab may lower IOP and result in regression of pathological neovascularization in the anterior segment in selected cases of NVG. Intravitreal administration of bevacizumab is currently widely used for the treatment of neovascular age-related macular degeneration, diabetic retinopathy and retinal vascular occlusions [11–13]. It was also found to be beneficial in NVG for IOP reduction, regression of neovascularization and relief of pain in several case series [2–7, 14–21]. Intravitreal bevacizumab is often administered in conjunction with panretinal photocoagulation and other medical and surgical interventions that aim to lower IOP. Increased aqueous humor levels of VEGF have been found in patients with NVG, and it is thought that the ciliary body, in addition to the retina, may produce VEGF and trigger ocular angiogenesis [1]. It follows that treating NVG with intracameral bevacizumab would effectively reduce VEGF levels [22]. Topical administration of bevacizumab was reported to be beneficial in the treatment of corneal neovascularization [23–25], and pharmacokinetic studies in animal models found that bevacizumab may be detected in the aqueous humor after topical administration of the drug, although the detected concentration was very low [9, 10]. Direct intracameral administration of bevacizumab was also reported to be beneficial in NVG in humans, resulting in a rapid regression of neovascularization. We hypothesized that topical administration of bevacizumab may penetrate to the anterior chamber and mimic lowdose intracameral injections of the drug. We found that topical bevacizumab administration (4 times a day for 2 weeks) resulted in a mean IOP reduction of 17.5%. Three of our patients demonstrated clinical regression of their neovascularization. According to our review of the literature, this is the first report of a positive effect of topical bevacizumab in the setting of NVG. We reviewed the relevant medical literature by searching MEDLINE (2001 to September 2013), using the keywords ‘topical or drops’ and ‘avastin or bevacizumab’ with the term ‘glaucoma’. The most important advantage of topical bevacizumab administration is the avoidance of intravitreal injections, which, although rarely, may nonetheless be associated with Topical Bevacizumab for NVG
sight-threatening complications such as endophthalmitis, traumatic cataract, uveitis and retinal detachment [13]. Moreover, the use of drops instead of intraocular injection would inevitably be more easily tolerated by many patients. In terms of safety, the treatment was generally well tolerated, with only mild and transient ocular adverse events noted in 3 patients. We were especially concerned about corneal epitheliopathy, which had been reported in patients receiving topical bevacizumab for corneal neovascularization (mostly during long-term use lasting more than 1 month) [24]. In the current study, the 3 recorded ocular adverse events were mild worsening of superficial punctate keratitis, mild corneal epithelial bullae (in a patient with preexisting corneal edema) and mild transient upper eyelid swelling. We allowed patients who had received previous intravitreal bevacizumab injections to enroll in the study, and 4 patients had been given this treatment 2–14 months prior to enrollment. It is thought that the effect of an intravitreal injection of bevacizumab in patients with NVG appears only within days after treatment [2, 4, 6, 19, 20], and therefore we believe the treatment effect demonstrated in this study is attributable to the topical bevacizumab administration rather than previous intravitreal bevacizumab injections given months prior to the study period. Systemic administration of bevacizumab has been reported to be associated with systemic adverse events, including thromboembolic events, especially during prolonged use with a high dosage. Therefore, we specifically instructed our patients to occlude their puncta in order to reduce systemic absorption. There was no occurrence of any serious adverse event or marked heart rate or blood pressure changes during the 2 weeks of treatment. In conclusion, topical bevacizumab may lower IOP and result in regression of neovascularization in patients with NVG. This case series included only 8 patients, and larger long-term studies are warranted to fully evaluate the effects of this treatment. Acknowledgements This study was supported by the Ministry of Health, Office of the Chief Scientist, Israel (grant 3-00000-4647) and the Lirot Association. The authors thank Esther Eshkol for editorial assistance and Galit Yair-Pur for obtaining the color photos.
Disclosure Statement The authors have no financial and/or proprietary interests to declare.
Pharmacology 2014;93:108–112 DOI: 10.1159/000358600
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ma. All ocular adverse events were mild in severity, transient and resolved after drug cessation or use of lubricating artificial tears.
References
112
9 Nomoto H, Shiraga F, Kuno N, Kimura E, Fujii S, Shinomiya K, et al: Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits. Invest Ophthalmol Vis Sci 2009;50:4807–4813. 10 Yoeruek E, Ziemssen F, Henke-Fahle S, Tatar O, Tura A, Grisanti S, et al: Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn. Acta Ophthalmol 2008;86:322–328. 11 Waisbourd M, Goldstein M, Loewenstein A: Treatment of diabetic retinopathy with antiVEGF drugs. Acta Ophthalmol 2011;89:203– 207. 12 Waisbourd M, Loewenstein A: The use of anti-angiogenic drugs for central retinal vein occlusion (in Hebrew). Harefuah 2010;149:243– 244, 261. 13 Waisbourd M, Loewenstein A, Goldstein M, Leibovitch I: Targeting vascular endothelial growth factor: a promising strategy for treating age-related macular degeneration. Drugs Aging 2007;24:643–662. 14 Kahook MY, Schuman JS, Noecker RJ: Intravitreal bevacizumab in a patient with neovascular glaucoma. Ophthalmic Surg Lasers Imaging 2006;37:144–146. 15 Yazdani S, Hendi K, Pakravan M: Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma. J Glaucoma 2007;16:437–439. 16 Costagliola C, Cipollone U, Rinaldi M, della Corte M, Semeraro F, Romano MR: Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma: a survey on 23 cases throughout 12-month follow-up. Br J Clin Pharmacol 2008;66:667–673. 17 Duch S, Buchacra O, Milla E, Andreu D, Tellez J: Intracameral bevacizumab (Avastin) for neovascular glaucoma: a pilot study in 6 patients. J Glaucoma 2009;18:140–143.
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18 Hasanreisoglu M, Weinberger D, Mimouni K, Luski M, Bourla D, Kramer M, et al: Intravitreal bevacizumab as an adjunct treatment for neovascular glaucoma. Eur J Ophthalmol 2009;19:607–612. 19 Moraczewski AL, Lee RK, Palmberg PF, Rosenfeld PJ, Feuer WJ: Outcomes of treatment of neovascular glaucoma with intravitreal bevacizumab. Br J Ophthalmol 2009; 93: 589–593. 20 Jonas JB, Golubkina L, Libondi T, Rensch F: Intravitreal bevacizumab for neovascular glaucoma. Acta Ophthalmol 2010; 88:e22– e23. 21 Sugimoto Y, Mochizuki H, Okumichi H, Takumida M, Takamatsu M, Kawamata S, et al: Effect of intravitreal bevacizumab on iris vessels in neovascular glaucoma patients. Graefes Arch Clin Exp Ophthalmol 2010; 248: 1601–1609. 22 Grover S, Gupta S, Sharma R, Brar VS, Chalam KV: Intracameral bevacizumab effectively reduces aqueous vascular endothelial growth factor concentrations in neovascular glaucoma. Br J Ophthalmol 2009;93:273–274. 23 Dastjerdi MH, Al-Arfaj KM, Nallasamy N, Hamrah P, Jurkunas UV, Pineda R 2nd, et al: Topical bevacizumab in the treatment of corneal neovascularization: results of a prospective, open-label, noncomparative study. Arch Ophthalmol 2009;127:381–389. 24 Kim SW, Ha BJ, Kim EK, Tchah H, Kim TI: The effect of topical bevacizumab on corneal neovascularization. Ophthalmology 2008; 115:e33–e38. 25 Koenig Y, Bock F, Horn F, Kruse F, Straub K, Cursiefen C: Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2009;247:1375–1382.
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1 Tripathi RC, Li J, Tripathi BJ, Chalam KV, Adamis AP: Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology 1998;105:232–237. 2 Iliev ME, Domig D, Wolf-Schnurrbursch U, Wolf S, Sarra GM: Intravitreal bevacizumab (Avastin) in the treatment of neovascular glaucoma. Am J Ophthalmol 2006; 142: 1054– 1056. 3 Silva Paula J, Jorge R, Alves Costa R, Rodrigues Mde L, Scott IU: Short-term results of intravitreal bevacizumab (Avastin) on anterior segment neovascularization in neovascular glaucoma. Acta Ophthalmol Scand 2006; 84:556–557. 4 Wakabayashi T, Oshima Y, Sakaguchi H, Ikuno Y, Miki A, Gomi F, et al: Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008; 115: 1571–1580, 1580.e1– 1580.e3. 5 Yazdani S, Hendi K, Pakravan M, Mahdavi M, Yaseri M: Intravitreal bevacizumab for neovascular glaucoma: a randomized controlled trial. J Glaucoma 2009;18:632–637. 6 Kotecha A, Spratt A, Ogunbowale L, dell’Omo R, Kulkarni A, Bunce C, et al: Intravitreal bevacizumab in refractory neovascular glaucoma: a prospective, observational case series. Arch Ophthalmol 2011;129:145–150. 7 Horsley MB, Kahook MY: Anti-VEGF therapy for glaucoma. Curr Opin Ophthalmol 2010;21:112–117. 8 Mizote M, Baba T, Hirooka K, Yamaji H, Shiraga F: Vascular endothelial growth factor concentrations in aqueous humor before and after subconjunctival injection of bevacizumab for neovascular glaucoma. Jpn J Ophthalmol 2010;54:242–244.
Pharmacology 2014;93:108–112 DOI: 10.1159/000358600
Topical Bevacizumab for Neovascular Glaucoma: A Pilot Study Michael Waisbourd a Gabi Shemesh a Shimon Kurtz a Rony Rachmiel a Elad Moisseiev a Shiri Zayit-Soudri a Anat Loewenstein a Irina Barequet b
a
Department of Ophthalmology, Tel Aviv Medical Center (affiliated to the Sackler Faculty of Medicine, Tel Aviv University), Tel Aviv, and b Goldschleger Eye Institute, Sheba Medical Center (affiliated to the Sackler Faculty of Medicine, Tel Aviv University), Tel Hashomer, Israel
Abstract Background/Aims: Bevacizumab (Avastin), an anti-vascular endothelial growth factor drug, has been successfully used in recent years to treat ocular pathologies, mostly by intravitreal administration. The aim of this study was to investigate the safety and efficacy of topically applied bevacizumab for the treatment of neovascular glaucoma (NVG). Methods: Patients with NVG were treated with topical bevacizumab (25 mg/ml) 4 times daily during 2 weeks. The following parameters were evaluated at baseline and on days 3, 7 and 14: visual acuity, slit-lamp examination, intraocular pressure (IOP), heart rate and systemic blood pressure. Iris neovascularization was documented using slitlamp color photos at baseline and on day 14. Results: Eight eyes of 8 patients with NVG were evaluated. After the 2-week treatment, mean IOP was lowered from 34.9 mm Hg (SD 12.8) at baseline to 28.8 mm Hg (SD 9.9) on day 14, representing a mean reduction of 6.1 mm Hg (17.5%). Three patients had clinical regression of their iris neovascularization. Ocular adverse events were transient and included mild upper eyelid swelling, mild exacerbation of superficial punctate keratitis and mild corneal epithelial bullae in an already edema-
© 2014 S. Karger AG, Basel 0031–7012/14/0934–0108$39.50/0 E-Mail [email protected] www.karger.com/pha
tous cornea. There were no serious systemic adverse events. Conclusions: Topical application of bevacizumab may lower IOP and result in regression of neovascularization in patients with NVG. © 2014 S. Karger AG, Basel
Introduction
Vascular endothelial growth factor (VEGF) is known to be a key player in the pathogenesis of neovascular glaucoma (NVG) [1], and intravitreal administration of the anti-VEGF drug bevacizumab (Avastin, Genentech, San Francisco, Calif., USA) has become a widely used treatment for patients with NVG, mostly in conjunction with or after completing panretinal photocoagulation. Intravitreal bevacizumab has been reported to result in regression of neovascularization of the iris and neovascularization of the angle and, consequently, reduction of intraocular pressure (IOP) [2–7]. Other studies showed that VEGF levels were significantly increased in the aqueous humor of patients with NVG [1], and subconjunctival injections of bevacizumab resulted in a decreased aqueous concentration of VEGF [8]. Furthermore, several animal studies showed that topically applied bevacizumab could reach detectable levels in the anterior chamber of the rabbit eye [9, 10]. This led us to hypothesize that topically Michael Waisbourd, MD Department of Ophthalmology, Tel Aviv Medical Center 6 Weizman Street Tel Aviv 64239 (Israel) E-Mail mwaisbourd @ hotmail.com
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Key Words Topical bevacizumab · Neovascular glaucoma · Anti-vascular endothelial growth factor
Table 1. Topical bevacizumab used in treating NVG: patients’ demographics and clinical parameters Patient Age, Sex Diagnosis No. years
Number of previous IVB injections (months prior to study1)
PRP treatment VA at VA at IOP at IOP at NV Adverse events (months prior to baseline day 14 baseline, day 14, regression study) mm Hg mm Hg
1 2 3 4
59 60 89 80
M M M F
CRVO, PXF OIS CRVO long-standing RD
2 (6) none 1 (11) none
complete (12) complete (4) complete (11) NA
20/400 LP NLP NLP
20/400 HM NLP NLP
21 38 47 48
16 28 36 36
– + + +
5 6 7 8
79 79 76 51
M F M M
long-standing RD CRAO failed TRD surgery PDR, TRD
3 (2) 2 (14) none none
NA complete (11) complete (8) complete (30)
NLP NLP HM NLP
NLP NLP HM NLP
42 46 12 25
43 36 15 20
– – – –
corneal epithelial bullae eyelid swelling mild SPK
IVB = Intravitreal bevacizumab; PRP = panretinal photocoagulation; VA = visual acuity; CRVO = central retinal vein occlusion; NV = neovascularization; M = male; F = female; PXF = pseudoexfoliation; OIS = ocular ischemic syndrome; LP = light perception; HM = hand movement; NLP = no light perception; RD = retinal detachment; CRAO = central retinal artery occlusion; TRD = tractional retinal detachment; SPK = superficial punctate keratitis; PDR = proliferative diabetic retinopathy; NA = not applicable, as it was impossible to perform panretinal photocoagulation in these patients. 1 Number of months since last intravitreal bevacizumab injection given prior to the study.
Materials and Methods
followed during this research. The study and data accumulation were carried out with approval from the Tel Aviv Medical Center Institutional Review Board. Informed consent for the research was obtained from each patient.
Results
Patients diagnosed with NVG secondary to various ocular pathologies were enrolled in the current study. Each subject’s past medical and ocular histories were reviewed and recorded. The study patients underwent baseline ophthalmic evaluation including best corrected visual acuity, slit-lamp examination of the anterior segment, corneal fluorescein staining for the evaluation of epithelial congruity, IOP measurements by Goldmann applanation tonometry and assessment of heart rate and systemic blood pressure levels. Each patient was then provided with a sterile bottle containing bevacizumab (75 mg/3 ml), which was prepared in the hospital’s pharmacy under sterile conditions. The patients were instructed to instill one drop (approximately 1.25 mg/0.05 ml bevacizumab per drop, equivalent to a concentration of 25 mg/ml) 4 times daily for 2 weeks into the affected eye. They were also taught to maintain strict punctal occlusion for at least 1 min after eyedrop instillation in order to reduce systemic drug absorption. Patients who were using other ocular drops were instructed to instill the bevacizumab drops first and then wait at least 5 min before instilling the other drops in order to prevent drug washout. Follow-up examinations were performed on days 3, 7 and 14 and included the same tests as those of the baseline examination. Slit-lamp color photography was performed at the baseline and final visits to document the extent of iris neovascularization. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were
Eight patients with NVG were enrolled. Table 1 details the patients’ demographics and clinical parameters. Six males and 2 females (mean age 71.6 years, range 51–89) received bevacizumab drops 4 times daily for a 2-week period. Patients’ glaucoma medications and other ocular topical treatments (e.g. artificial tears) remained unchanged during the study period. Visual acuity remained unchanged in 7 patients and was slightly improved in 1 patient (from light perception to hand motion detection). Overall, IOP decreased from a mean of 34.9 mm Hg (SD 12.8) at baseline to 28.8 mm Hg (SD 9.9) on day 14, representing a mean reduction of 6.1 mm Hg (17.5%). Figure 1 illustrates IOP curves for each patient, showing the value of IOP measured by applanation at each visit. Clinical regression of iris neovascularization was noted in 3 patients during the 14 days of follow-up, whereas in the other 5 patients, no substantial change in the extent of the anterior segment neovascularization was noted. Figure 2 presents color iris photographs showing partial regression of iris neovascularization and marked improvement of conjunctival injection over the 2-week follow-up in 2 patients.
Topical Bevacizumab for NVG
Pharmacology 2014;93:108–112 DOI: 10.1159/000358600
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applied bevacizumab may reduce the levels of VEGF in the anterior chamber and result in local regression of pathological neovascularization with subsequent lowering of IOP in patients with NVG.
50 Patient 1 Patient 2
IOP (mm Hg)
40
Patient 3
Color version available online
60
Patient 4
30
Patient 5 Patient 6
20
Patient 7 Patient 8
10
Fig. 1. IOP curves of 8 patients with NVG
who received topical bevacizumab (25 mg/ ml) for 2 weeks. Visit 1: baseline; visit 2: day 3; visit 3: day 7; visit 4: day 14.
Visit 1
Visit 2
Visit 3
Visit 4
Fig. 2. The effect of topical bevacizumab (25 mg/ml) in patients with NVG after 2 weeks. a–d Patient 1: iris neovascularization partially regressed and IOP fell from 38 to 28 mm Hg. e, f Patient 2: marked improvement of conjunctival congestion and lowering of IOP from 47 to 36 mm Hg.
a
b
c
d
e
f
No serious systemic adverse events were recorded during the study. The mean heart rate and systemic blood pressure measurements obtained from the entire study group remained stable during the study; they changed from 67.4 to 65.7 beats/min and from 153/76 to 148/75 110
Pharmacology 2014;93:108–112 DOI: 10.1159/000358600
mm Hg, respectively. Few ocular adverse events were noted during the study. One patient had a mild upper eyelid swelling; 1 patient had mild exacerbation of superficial punctate keratitis, and mild corneal epithelial bullae were noted in one eye of a patient with preexisting corneal edeWaisbourd et al.
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Color version available online
0
Discussion
The results of this pilot study suggest that short-term use of topical bevacizumab may lower IOP and result in regression of pathological neovascularization in the anterior segment in selected cases of NVG. Intravitreal administration of bevacizumab is currently widely used for the treatment of neovascular age-related macular degeneration, diabetic retinopathy and retinal vascular occlusions [11–13]. It was also found to be beneficial in NVG for IOP reduction, regression of neovascularization and relief of pain in several case series [2–7, 14–21]. Intravitreal bevacizumab is often administered in conjunction with panretinal photocoagulation and other medical and surgical interventions that aim to lower IOP. Increased aqueous humor levels of VEGF have been found in patients with NVG, and it is thought that the ciliary body, in addition to the retina, may produce VEGF and trigger ocular angiogenesis [1]. It follows that treating NVG with intracameral bevacizumab would effectively reduce VEGF levels [22]. Topical administration of bevacizumab was reported to be beneficial in the treatment of corneal neovascularization [23–25], and pharmacokinetic studies in animal models found that bevacizumab may be detected in the aqueous humor after topical administration of the drug, although the detected concentration was very low [9, 10]. Direct intracameral administration of bevacizumab was also reported to be beneficial in NVG in humans, resulting in a rapid regression of neovascularization. We hypothesized that topical administration of bevacizumab may penetrate to the anterior chamber and mimic lowdose intracameral injections of the drug. We found that topical bevacizumab administration (4 times a day for 2 weeks) resulted in a mean IOP reduction of 17.5%. Three of our patients demonstrated clinical regression of their neovascularization. According to our review of the literature, this is the first report of a positive effect of topical bevacizumab in the setting of NVG. We reviewed the relevant medical literature by searching MEDLINE (2001 to September 2013), using the keywords ‘topical or drops’ and ‘avastin or bevacizumab’ with the term ‘glaucoma’. The most important advantage of topical bevacizumab administration is the avoidance of intravitreal injections, which, although rarely, may nonetheless be associated with Topical Bevacizumab for NVG
sight-threatening complications such as endophthalmitis, traumatic cataract, uveitis and retinal detachment [13]. Moreover, the use of drops instead of intraocular injection would inevitably be more easily tolerated by many patients. In terms of safety, the treatment was generally well tolerated, with only mild and transient ocular adverse events noted in 3 patients. We were especially concerned about corneal epitheliopathy, which had been reported in patients receiving topical bevacizumab for corneal neovascularization (mostly during long-term use lasting more than 1 month) [24]. In the current study, the 3 recorded ocular adverse events were mild worsening of superficial punctate keratitis, mild corneal epithelial bullae (in a patient with preexisting corneal edema) and mild transient upper eyelid swelling. We allowed patients who had received previous intravitreal bevacizumab injections to enroll in the study, and 4 patients had been given this treatment 2–14 months prior to enrollment. It is thought that the effect of an intravitreal injection of bevacizumab in patients with NVG appears only within days after treatment [2, 4, 6, 19, 20], and therefore we believe the treatment effect demonstrated in this study is attributable to the topical bevacizumab administration rather than previous intravitreal bevacizumab injections given months prior to the study period. Systemic administration of bevacizumab has been reported to be associated with systemic adverse events, including thromboembolic events, especially during prolonged use with a high dosage. Therefore, we specifically instructed our patients to occlude their puncta in order to reduce systemic absorption. There was no occurrence of any serious adverse event or marked heart rate or blood pressure changes during the 2 weeks of treatment. In conclusion, topical bevacizumab may lower IOP and result in regression of neovascularization in patients with NVG. This case series included only 8 patients, and larger long-term studies are warranted to fully evaluate the effects of this treatment. Acknowledgements This study was supported by the Ministry of Health, Office of the Chief Scientist, Israel (grant 3-00000-4647) and the Lirot Association. The authors thank Esther Eshkol for editorial assistance and Galit Yair-Pur for obtaining the color photos.
Disclosure Statement The authors have no financial and/or proprietary interests to declare.
Pharmacology 2014;93:108–112 DOI: 10.1159/000358600
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ma. All ocular adverse events were mild in severity, transient and resolved after drug cessation or use of lubricating artificial tears.
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