A COMPARATIVE EVALUATION OF EFFICACY AND TOLERABILITY OF FIXED DRUG COMBINATION OF BRIMONIDINE AND TIMOLOL WITH TIMOLOL MONOTHERAPY IN PATIENTS WITH PRIMARY OPEN-ANGLE GLAUCOMA: AN OPEN LABELED PROSPECTIVE STUDY Dissertation submitted to THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY in partial fulfillment of the regulations for the award of the degree of M.D. (PHARMACOLOGY) BRANCH – VI GOVT. STANLEY MEDICAL COLLEGE & HOSPITAL THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY CHENNAI, INDIA MAY 2019 1 CERTIFICATE This is to certify that this dissertation entitled “A comparative evaluation of efficacy and tolerability of Fixed drug combination of Brimonidine and Timolol with Timolol monotherapy in patients with Primary Open-Angle Glaucoma: An Open Labeled Prospective Study” by the candidate Dr.SP.SUBAHAN, for M.D. (Pharmacology) is a bonafide record of the research work done by him under the guidance of Dr. R.JEYALALITHA, M.D., Professor, Department of Pharmacology, Government Stanley Medical College, during the period of study (2016- 2019), in the Department of Pharmacology, Government Stanley Medical College,Chennai-01. I also certify that this dissertation is the result of the independent work on the part of the candidate. Dr.R.Jeyalalitha, M.D., Dr.M.Kulandaiammal, D.G.O., M.D., Professor, Professor & Head of the Department Department of Pharmacology Department of Pharmacology Govt.Stanley Medical College. Govt.Stanley Medical College. Dr.S.Ponnambala Namasivayam, M.D., D.A., DNB Dean Govt.Stanley Medical College Chennai. 2 DECLARATION I hereby declare that this dissertation entitled in “A comparative evaluation of efficacy and tolerability of Fixed drug combination of Brimonidine and Timolol with Timolol monotherapy in patients with Primary Open-Angle Glaucoma: An Open Labeled Prospective Study” was written by me in the Department of Pharmacology, Government Stanley Medical College and Hospital, Chennai under the guidance and supervision of Dr.R.Jeyalalitha, M.D., Professor, Department of Pharmacology, Government Stanley Medical College, Chennai – 600 001. This dissertation is submitted to The Tamilnadu Dr. M.G.R. Medical University, Chennai in partial fulfillment of the university regulations for the award of Degree of M.D., Pharmacology(Branch -VI) Examination to be held in May 2019. Date: Place: Chennai Dr.SP.Subahan 3 ACKNOWLEDGEMENT I express my sincere gratitude to Dr.S.Ponnambala Namasivayam M.D., D.A., DNB., Dean, Govt. Stanley Medical College for permitting me to undertake this research work as a part of my MD curriculum. I would like to convey my gratitude and indebtedness to Dr.M.Kulandaiammal D.G.O., M.D., Professor and Head of the Department of Pharmacology, Govt. Stanley Medical College for her sincere advice, unfailing support and attention throughout the study. I owe my sincere thanks and appreciation to my guide Dr.R.Jeyalalitha M.D., Professor, Department of Pharmacology, Govt. Stanley Medical College, Chennai for her inspirational guidance and encouragement with which the dissertation has been prepared. I would like to convey my gratitude to Dr.Baskar, M.S,D.O., Professor and Head of the Department of Ophthalmology, Govt.Stanley Medical College for permitting me to carry out this study in Ophthalmology department, Govt.Stanley medical college. I express my sincere thanks to my Professors Dr.G.Hemavathy,M.D., Dr.R.Sivagami, M.D., and Dr.Baskaran, M.D., Department of Pharmacology for their constant support and advice. 4 I am thankful to Dr. M.Mohana Lakshmi D.G.O.,M.D., Dr.B. Kalaimathi. M.D., Dr.N.Asvini M.D., Dr.M.Prakash M.D., Dr.M.Sangavai M.D., Dr.B.Pushpa M.D., Dr.K.Thamayanthi M.D., Dr. C.R.Anuradha D.G.O., M.D., Dr.J.Sam Anbu Sahayam D.L.O., M.D., Dr.R.Divakar M.D., Dr.Renuka Devi M.D., and Dr.Dharani Sudha M.D., for their unconditional co-operation and help. I thank Dr.A.Preethi, Dr.G.vanitha, Dr.R.Punitha, Dr.E.Tamilmathy and Dr.J.Vineeta Debbie Nesam, my fellow postgraduates for their help throughout this study. I wish to place on record my gratitude to my parents and my family members for creating a congenial atmosphere and support when it was needed. I thank all the staffs of the Department of pharmacology, Stanley medical college, for their cooperation in the completion of my study. Finally I thank all my patients for willingly submitting themselves for this study. 5 CERTIFICATE-II This is to certify that this dissertation work titled “A comparative evaluation of efficacy and tolerability of Fixed drug combination of Brimonidine and Timolol with Timolol monotherapy in patients with Primary Open-Angle Glaucoma: An Open Labeled Prospective Study” of the candidate Dr.SP.Subahan with registration number 201616052 for the award of M.D. Pharmacology in the branch of VI. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 5 percentage of plagiarism in the dissertation. Guide & Supervisor sign with Seal Dr.R.Jeyalalitha, M.D., Professor, Department of Pharmacology Govt.Stanley Medical College. 6 7 8 CONTENTS S.No Title Page No 1. Introduction 12 2. Review of literature 15 3. Aim and Objectives 69 4. Methods 71 5. Results 81 6. Discussion 92 7. Conclusion 99 8. Bibliography 100 9. Annexures 107 9 ABBREVIATIONS AAO -American Academy of Ophthalmology ALT - Argon Laser Trabeculoplasty CAIs -Carbonic Anhydrase Inhibitors CB -Ciliary Body CSLT -Confocal Scanning Laser Tomography DLT -Diode Laser Trabeculoplasty FDC -Fixed Drug Combination HFA -Humphry Field Analyser HRT -Hiedelberg Retinal Tomography IOP -Intra Ocular Pressure LTG -Low Tension Glaucoma NFLA -Nerve Fibre Layer Analyser NMDA -N Methyl-D-Aspartate NTG -Normal Tension Glaucoma 10 OCT -Optical Coherence Tomography OHTS -Ocular Hypertension Treatment Study PAC -Primary Angle Closure PACG -Primary Angle Closure Glaucoma POAG -Primary Open Angle Glaucoma RGC -Retinal Ganglion Cell SL -Swalbe’s Line SS -Scleral Spur TM -Trabecular Meshwork 11 INTRODUCTION Glaucoma, an optic neuropathy, is a worldwide leading cause of visual impairment and blindness1. It is a neurodegenerative disease associated with loss of Retinal Ganglion Cells and a raised intraocular pressure2 (IOP) which is the modifiable risk factor for glaucoma. Glaucoma is an important cause of blindness in the developing world and a major health burden in the developed world. Glaucoma accounts for up to 8.2% of total visual loss in the world. It is also the leading cause of visual loss in India3. More than 85 percent of cases of glaucoma are remaining undiagnosed in India. Raised intraocular pressure is an important known risk factor for the progression of visual field loss4 in patients with glaucoma. Primary open angle glaucoma5 (POAG), is characterized by chronically elevated IOP with optic neuropathy and the cause is unknown for the elevated IOP. It results from defective drainage of aqueous humor through the trabecular meshwork and uveoscleral pathways. Aqueous humor is formed by ciliary body and provides nourishment to anterior segment structures6. Regardless of the cause of the disease, the aim of treatment is to control IOP. Many clinical trials have proved that controlling IOP is an effective measure and prevents the development of glaucoma in patients with ocular hypertension and arrests the progression of established glaucoma. 12 Reduction of IOP with less complications or adverse effects remains the mainstay therapy for the first-line treatment of glaucoma7. Many anti glaucoma drugs achieve this control of IOP in glaucoma patients with a once- daily dose of a single drug. The preferred method is topical monotherapy8. Initial management of glaucoma includes topical medications or laser treatment to control IOP. Frequently, more than one drug is required to achieve adequate control of IOP. Two or more medications are needed to reach a target IOP9 to arrest further visual loss in many patients with POAG. The medical treatment approved for glaucoma management is IOP- reducing drugs10. The drugs commonly used to reduce IOP in glaucoma include topical prostaglandin analogues like bimatoprost, beta-blockers like timolol, alpha-agonists like brimonidine, carbonic anhydrase inhibitors like dorzolamide, and parasympathomimetics. The prostaglandin analogues are first choice of drugs used as initial monotherapy once-daily. In recent years, fixed drug combinations11 have been approved for treatment of glaucoma. The available fixed combination drugs in the market are timolol 0.5% combined with bimatoprost, dorzolamide or brimonidine. The benefits of fixed drug combinations are well achieved target IOP control, reduction in total amount of drug and preservative instilled per day, economic benefits, better tolerability and adherence, avoiding the washout effect resulting from simultaneous instillation of multiple medications concurrently. And also, this fixed drug combinations primarily promote the compliance of patients and persistence with treatment12. 13 Only IOP lowering treatment is not enough to prevent progressive vision loss as glaucoma is a multifactorial disorder. RGC damage and death are the final outcomes in untreated glaucoma. This urges an alternative treatment approach - neuroprotection approach to manage this problem more efficiently. Neuroprotection13 approach prevents neuronal injury or promotes neuronal recovery and protects the RGC from glaucomatous injuries. Neuroprotective drugs are useful to prevent the damage of RGCs and destruction of optic nerve fibers. NMDA receptor antagonists, antioxidants, calcium channel blockers, nitric oxide synthase antagonists and gene therapy are used as neurotropic drugs14. In Ocular Hypertension Treatment Study, more than 41% of the patients needed two or more medications after 4 years to achieve the target IOP. In Collaborative Initial Glaucoma Treatment Study, 80% of the patients required two or more medications after 2 years15. Therefore this study is undertaken with the aim to compare and evaluate the efficacy and safety of a fixed drug combination of 0.2% brimonidine and 0.5% timolol with the effect of 0.5% timolol administered as monotherapy in patients with POAG.