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Original Article
Arshad Ali Lodhi, Murtaza, Munawar Ahmed, Noman Ahmed, Ghulam Haider,
Sameen Afzal Junejo, Mustafa Kamal
Pak J Ophthalmol 2015, Vol. 31 No. 3 Purpose: To find the efficacy of topical tetracycline in corneal neo-
authors affiliations vascularization. ….………………………. Material and Methods: In this prospective observational clinical analysis,
patients more than fifteen year's age of either sex were enrolled. Anterior Correspondence to: segment slit lamp examination was performed. Fluorescein 1% dye and rose Sameen Afzal Junejo bengal were used to stain cornea at the bed and margins simultaneously. The Department of Ophthalmology. area of corneal vascularization was measured in mm using 0.5% fluorescein Liaquat University of Medical dye. The percentage of neovascularized corneal areas to the entire cornea was and Health Sciences/Jamshoro, Sindh Pakistan Emai Result: Out of twenty eight patients twenty one completed follow up period of
four months. Among 21 patients males were 10 (47.6%), and females 11 (52.38%) with unilateral and bilateral corneal neo-vascularization. 15 (71.42%) responded well and showed reduction in corneal new vessels from 7 mm pre- treatment to 2 mm (overall) post treatment at the end of fourth month. six patient showed poor or no response due to extended fibrosis. Conclusion: Topical tetracycline has remained quite instrumental in reducing
superficial epithelial and sub-epithelial corneal new vessels. Key Words: Cornea; Neovascularization; Tetracycline; Therapeutic effect.
cular neovascularization is the abnormal extended use can result in to unavoidable side effects growth of blood vessels in the retina, choroid and complications.1,2 O and cornea. They can lead to many Tetracycline is a second generation long acting complications like fibrosis, scarring and blindness. non selective antibiotic.2,3 Topical application inhibits Common causes of corneal neovascularization are corneal lysis, treats corneal ulcers and encourages blepharitis, keratitis, corneal graft rejection, chemical corneal epithelium healing.4,5 Apart from this, injuries and improper or prolonged use of contact tetracycline has also been proved to be quite effective lenses.1 The main source of superficial corneal in inhibiting corneal new vessels by inhibiting matrix neovascularization arises from conjunctiva. The metalloproteinase (MMP) activity.6,7 superficial vessels adopt the pattern of diffuse tree branches and are usually observed passing through Topically induced drugs have become more the corneo-scleral junction invading anterior layers of successful and better effective in the treatment of cornea up to substantia propria. While deep corneal ocular surface disorders.8 Tetracycline or its derivative vessels are having straight course originate from deep preparations (doxycycline, minocycline) accelerate scleral vessels and penetrate the deeper corneal layers corneal wound healing and promote reduction in including corneal stroma and beyond. Antibiotics, corneal new vessels by inhibiting MMP activity.9, 10 lasers and other treatment have limited approach. The objective of this study was to document the Steroids are used to combat with this problem but Pakistan Journal of Ophthalmology Vol. 31, No. 3, Jul – Sep, 2015 150

ARSHAD ALI LODHI, et al therapeutic effect of topical tetracycline on superficial subjects belonged to rural areas. The characteristics of corneal neovascularization. enrolled patients is mentioned in table 1. Seven (25.0%) subjects were lost to follow up. Out of remaining twenty one, there was significant MATERIAL AND METHODS
reduction in corneal neo-vascularization in 15 (71.42%) This prospective observational clinical analysis was performed at Liaquat University Eye hospital Hyderabad, Sindh of Liaquat University of Medical and Health Sciences / Jamshoro Pakistan from June 2011 to May, 2015. Inclusion criteria: The subjects of more than fifteen years of age from both genders with unilateral or bilateral superficial (epithelial and sub-epithelial bowman associated with ocular surface disorders without any history of ocular surgery were included. All the enrolled cases were examined at outpatient department of the tertiary eye care center. Detailed history and verbal consent of the patients was obtained. Anterior segment was examined using slit lamp bio-microscope. Corneal staining was done with fluorescein 1% dye. Rose Bengal stains were used to stain devitalized cornea. The area of corneal vascularization was measured in mm by using 0.5% fluorescein under cobalt blue filter on slit lamp bio-microscope by the same ophthalmologist. The percentage of neovascularized corneal areas to the entire cornea was calculated. The primary treatment of different antibiotics and steroids was stopped. The secondary treatment was started with tetracycline (HCL-USP 5 mg) ophthalmic gel thrice a day. Tetracycline thus used during this study pharmaceutical company. The area of corneal epithelial defect with new vessels was measured on 15th day, one month and every two months for four months. All the subjects were requested to complete the treatment follow up criteria of this study. Statistical Package of Social Science (SPSS) version 14 was used for statistical data analysis on corneal vascularization. Out of 28, seven patients did not complete the 4 months follow up and will not be discussed in the The student – t test was used to evaluate the data. results. In twenty one patients who completed follow The mean age of the patients was 39.38 years. The up, male were 10 (47.6%), female 11 (52.38%) with results of treatment were quite significant (2-tailed), unilateral and bilateral corneal neo-vascularization with the P value 0.002. Standard deviation was were registered for this study (Fig. 1-3). Most of the 1.21253; confidence interval of the difference was 151 Vol. 31, No. 3, Jul – Sep, 2015 Pakistan Journal of Ophthalmology ROLE OF TETRACYCLINE IN CORNEAL NEOVASCULARIZATION 95%.The documented overall reduction in new vessels issue. We could not compare the results of our study was from 7 mm to 2 mm after four months of with other national studies. There is no doubt a need treatment (Fig. 4 - 6). One (4.47%) lady recovered for advanced study and research on the efficacy of moderately and remaining five (23.81%) did not tetracycline in different ocular diseases particularly respond to the treatment due to extended fibrosis corneal neovascularization. although the symptoms were relieved. CONCLUSION
Tetracycline has proved itself to be more promising in Corneal neovascularization (CNV) is a sight- threatening condition. Most often it develops neovascularization thus enhancing the inhibitory secondary to inflammatory conditions and ocular effects of angiogenesis. surface disorders. Corneal trauma due to chemical burns causes severe corneal neovascularization.11 In this study two patients developed corneal Author's Affiliation
neovascularization after alkali burn, which could not Dr. Arshad Ali Lodhi improve inspite of abrupt treatment with tetracycline Department of Ophthalmology and associated medications. Liaquat University of Medical and Health Various sources promote neovascularization i.e. Sciences/Jamshoro, Sindh/Pakistan growth factors, prostaglandins and interleukins. The process of corneal new vessels formation consists of Department of Ophthalmology two steps. First is the vascular endothelial growth Liaquat University of Medical and Health factor (VEGF) related to proliferation of vascular Sciences/Jamshoro, Sindh/Pakistan endothelium. Second step reformation of extracellular matrix followed by activation of cytokines. Corneal Dr. Munawar Ahmed neovascularization due to alkali burns is related to Department of Ophthalmology inflammation. In response to a chemical burn the Liaquat University of Medical and Health inflammatory cells release cytokines and MMPs. There Sciences/Jamshoro, Sindh/Pakistan is also a variety of compounds supposed to inhibit corneal new vessels. Such anti angiogenic factors are Department of Ophthalmology non-steroidal anti-inflammatory agents, steroids and Liaquat University of Medical and Health immuno suppressives.12, 13 Sciences/Jamshoro, Sindh/Pakistan The treatment of choice in corneal neovasculari- Dr. Ghulam Haider zation is topical use of corticosteroids. But due to their Department of Ophthalmology disastrous side effects and complications now a days Liaquat University of Medical and Health have got restricted application. 14 In our study steroids Sciences/Jamshoro, Sindh/Pakistan use was not documented in any registered subject. Dr. Sameen Afzal Junejo Department of Ophthalmology The efficacy of tetracycline depends upon its Liaquat University of Medical and Health concentration, route of application, and patient's Sciences/Jamshoro, Sindh/Pakistan acceptance. The recommended dosage of tetracycline is absolutely non-toxic to the corneal surface and Dr. Mustafa Kamal adnexa. In our study tetracycline with the dosage of Department of Ophthalmology 5 mg was used topically three times a day. Its effect on Liaquat University of Medical and Health cornea is biological oriented rather than antimicrobial. Sciences/Jamshoro, Sindh/Pakistan According to the recent global research, tetracycline also acts to suppress tumor growth, angiogenesis, resorption of bone.15, 16 Role of Authors
Dr. Arshad Ali Lodhi Limitations to This Study
Drafting, methodology, patient's selection, and In our area not much work has yet been done on this literature search. Pakistan Journal of Ophthalmology Vol. 31, No. 3, Jul – Sep, 2015 152 ARSHAD ALI LODHI, et al doxycycline on neovascularization in a rat corneal alkali Maintained the post treatment follow up record of all burn model of angiogenesis, "Curr Eye Res. 2008; 33: the subjects who full filed regular follow up criteria of 7. Cox CA, Amaral J, Salloum R,
Dr. Munawar Ahmed Drafting, methodology, patient's selection, and Doxycycline's effect on ocular angiogenesis: an in vivo literature search. analysis. Ophthalmology. 2010; 117: 1782–91. 8. Samtani S, Amaral J, Campos MM,
Doxycycline-mediated inhibition of choroidal Performing ocular examinations and data collection. neovascularization, Invest Ophthalmol Vis Sci. 2009; 50: 9. Anumolu SS, DeSantis AS, Menjoge AR,
Performing ocular examinations and data collection. Doxycycline loaded Dr. Sameen Afzal Junejo poly (ethylene glycol) hydrogels for healing vesicant- Selection of patients, examination treatment and induced ocular wounds. Biomaterials. 2010; 31: 964–74. 10. Su W, Li Z, Lin M, et al. The effect of doxycycline
temperature-sensitive hydrogel on inhibiting the Dr. Mustafa Kamal corneal neovascularization induced by bFGF in rats. Maintained the post treatment follow up record of all Graefes Arch Clin Exp Ophthalmol. 2011; 249: 421–7. the subjects who full filed regular follow up criteria of 11. Wagoner MD. Chemical injuries of the eye: current
concepts in pathophysiology and therapy, Surv Ophthalmol. 1997; 41: 275–313. 12. Li T, Hu A, Li S, Luo Y, Huang
KH906, a recombinant human VEGF receptor fusion protein, is a new effective Lim P, Fuchsluger TA, Jurkunas UV. "Limbal stem cell
deficiency and corneal neovascularization", Semin
topical treatment for corneal neovascularization," Mol Ophthalmol. 2000; 24: 139-48. Vis. 2011; 17: 797–803. 13. Ma DH, Chen JK, Kim WS, Hao YX, Wu HC, et al.
Moses MA, Harper J, Folkman J. "Doxycycline
treatment for lymphangioleiomyomatosis with urinary
"Expression of matrix metalloproteinases 2 and 9 and monitoring for MMPs," N Engl J Med. 2006; 354: 2621–2. tissue inhibitors of metalloproteinase 1 and 2 in inflammation-induced neovascularization, Lindeman JH, Abdul-Hussien H, van Bockel JH, et al.
Ophthalmic Res. 2001; 33: 353–62. metalloproteinase-9 inhibition in patients with an 14. De Paiva CS, Corrales RM, Villarreal AL, Farley WJ, Li
abdominal aneurysm: doxycycline selectively depletes DQ, et al. Corticosteroid and doxycycline suppress
aortic wall neutrophils and cytotoxic T cells, MMP-9 and inflammatory cytokine expression, MAPK "Circulation. 2009; 119: 2209–16. activation in the corneal epithelium in experimental dry eye," Exp Eye Res. 2006; 83: 526–35. Villarreal FJ, Griffin M, Omens J, Early short-term treatment with
15. Federici TJ. The non-antibiotic properties of
doxycycline modulates postinfarction left ventricular tetracyclines: Clinical potential in ophthalmic disease. remodeling, Circulation. 2003; 108: 1487–92. Pharmacol Res. 2011; 64: 614–23. 16. Liang D, Yan SL, Lin ML, Li YP, Ma HJ, et al.
Ralph RA. Tetracyclines and the treatment of corneal
stromal ulceration: a review, Cornea. 2000; 19: 274–7.
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angiogenesis. Curr Eye Res. 2008; 33: 653–60. 153 Vol. 31, No. 3, Jul – Sep, 2015 Pakistan Journal of Ophthalmology

Source: http://www.pjo.com.pk/31/3/8.%20Arshad%20Ali%20Lodhi.pdf

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