NEUROPROTECTIVE EFFECT OF BETAXOLOL, DORZOLAMIDE, BRIMONIDINE AND GINKGO BILOBA IN PATIENTS WITH NORMAL TENSION GLAUCOMA

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1 NEUROPROTECTIVE EFFECT OF BETAXOLOL, DORZOLAMIDE, BRIMONIDINE AND GINKGO BILOBA IN PATIENTS WITH NORMAL TENSION GLAUCOMA Veljko Andreić, MD PhD Ophthalmology Eye clinic, Clinical Center of Vojvodina, Hajduk Veljkova 1-5, Novi Sad 21000, Serbia Novi Sad, (Presented on World Glaucoma Congress in Hong Kong in 2015.)

2 Corresponding Author: Veljko Andreić, Vase Stajića 14, Novi Sad, Serbia (Phone: , Keywords: normal, low, tension, glaucoma, neuroprotection, brimonidine, ginkgo, dorsolamide, betaxolol.

3 ABSTRACT Aim: Finding the best therapeutic approach for NTG among potentially neuroprotective drugs. Also, this study is evaluating local and systemic adverse effects of these drugs. Material and Methods: Study enrolled 215 patients/eyes with follow up period up to 18 months, forming equal six groups divided in to pairs of three, where either brimonidine, betaxolol or dorzolamide were administered as local monotherapy, or paired with ginkgo biloba administered systemically. An automatic perimeter with central 30 degrees has been used as a method of control to follow up retina sensitivity changes on 0, 6, 12 and 18 month. Other measured parameters were: IOP, visual acuity, C/D ratio of the optic nerve head and blood pressure. Results: A highest retina sensitivity increase was in both brimonidine groups. Only brimonidine with ginkgo biloba had significant change of both MD (-7.94±5.9 db on 0 month, -6.17±6.5 db on 18 month, p<0.05) and PSD value (7.04±4.0 on 0 month, 5.99±4.2 on 18 month, p<0.05). Visual acuity decrease in group treated with betaxolol and ginkgo biloba (0.84±0.24 on 0 month, 0.81±0.27 on 18 month, p<0.05) and increase in group treated with brimonidine monotherapy (0.9±0.11 on 0 month, 1.0±0.11 on 18 month, p<0.05). C/D got worse in group treated with betaxolol and ginkgo biloba (0.57±0.23 on 0 month, 0.64±0.2on 18 month, p<0.05). Conclusion: A local brimonidine therapy combined with ginkgo biloba given orally has highest retina sensitivity improvement in patients with NTG. Brimonidine with ginkgo biloba could be recommended for NTG therapy in duration of at least 18 months. Abbreviations: Normal-tension glaucoma - NTG Intraocular pressure - IOP Cup/Disc ratio of optic nerve head - C/D Mean Deviation - MD Pattern standard deviation - PSD Analysis of variance - ANOVA 1

4 INTRODUCTION Normal-tension glaucoma (NTG) is a chronic progressive optic neuropathy followed by optic nerve and retinal nerve fiber layer morphological changes. Compared to other types of glaucoma the intraocular pressure in NTG is always in normal range 1. Patients who suffer from NTG have compromised peripheral circulation. A headache, numbness of fingers, cold limbs and low blood pressure are often present in those patients. Capillary blood flow in retina is also reduced in patients with NTG 2. A disease is asymptomatic until severe visual field loss occurs 3. Despite a vascular etiology and normal values of IOP, therapeutic guidelines for NTG are the same as for primary open-angle glaucoma 1. The aim of glaucoma therapy is focused on IOP lowering. On the other hand, a neuroprotective effect of glaucoma medication could be addressed to some other pharmacological properties which are not primarily connected to IOP lowering 4. The goal of neuroprotection is to prevent neuron cells death by blocking apoptosis 5. Through neuroprotection, surrounding healthy neurons remain intact and retina sensitivity could be improved 6. These changes in retina sensitivity can be detected with automated perimeter 1 and if improvement in sensitivity occurs it could be the evidence of neuroprotection of investigated drug. This is an indirect way to prove a neuroprotection through changes in retina function and that kind of approach was applied in this research. The aim of this study was to examine therapeutic effects of three, potentially neuroprotective, topical drugs (betaxolol, dorsolamide and brimonidine) used in everyday clinical practice. These drugs were used alone or in combinations with ginkgo biloba administered oraly. This study also evaluated retinal sensitivity, IOP, visual acuity, C/D ratio of optic nerve head, blood pressure and side effects of tested drugs through 18 months period. All potentially neuroprotective eye drops for glaucoma were tested. Betaxolol is a cardio selective calcium channel and β 1 blocator. Several studies showed its positive effect in NTG patients 7,8. Dorsolamide is a carboanhidrase inhibitor which improve ocular circulation by increasing elasticity and velocity of erythrocytes in blood vessels 9,10. Brimonidine is α 2 adrenergic agonist with proven neuroprotective effect in animal model but it is still not proven in humans 11. Ginkgo biloba is not the antiglaucoma drug but its benefitial effect is shown in few studies on ageing 2

5 processes, circulatory and neurodegenerative diseases 12,13,14. Ginkgo also improves retina sensitivity in patients with NTG 15. Combining different antiglaucoma medication with ginkgo biloba extract (EGB) could eventually get a sinergistic neuroprotective effect in NTG. MATERIAL AND METHODS This was a prospective, open labeled, randomized study conducted in University Eye Clinic, Clinical Center of Vojvodina, Novi Sad, Serbia, from 2009 to The study enrolled Caucasians, 215 patients/eyes of which 24 patients were excluded due to drug side effects. The follow up period was 18 months for every patient. All patients signed an informed consent. This research was approved by Ethic Committee of Clinical Center of Vojvodina and Ethic Committee of Medical Faculty of Novi Sad, Serbia. A central 30 degrees standard automated perimetry was performed to all patients. An automated perimetry testing is a fundamental diagnostic procedure in glaucoma 16. This study followed important parameters - deviations of retina sensitivity. The average of these deviations across all test locations is referred to as the Mean Deviation (MD). Subjects, who were able to see dimmer stimuli than others of similar age and race, have positive values for their MD, while subjects who require brighter stimuli have negative MD values. MD values for reliable tests typically range from +2 db to -30 db. Pattern standard deviation (PSD) measures irregularity by summing the absolute value of the difference between the threshold value for each point and the average visual field sensitivity at each point (equal to the normal value for each point + the MD). Visual fields with the age-normal sensitivity at each point will have a PSD of 0, as visual fields in which each point is uniformly depressed from the age-normal value. Thus, the largest PSD will be registered for focal, deep visual field defects. Near-normal and severely damaged visual fields will both have low PSD 17. Visual acuity was measured with log Mar scale. An IOP was measured at 8AM and 12AM on scheduled controls with Goldman tonometer. Cup/disc ratio (C/D) was evaluated with 90D lens. Both IOP and C/D were measured by same ophthalmologist. A systolic and diastolic blood pressure was measured in sitting position always on the right hand. Statistical analysis was done in MS Excel using ANOVA and student t-test with 95% confidence interval. 3

6 Six groups of a 30 patients each were formed. In three groups a local monotherapy of betaxolol, dorzolamide or brimonidine has been administered. In other three groups a local monotherapy of betaxolol, dorzolamide ot brimonidine were combined with gingko biloba administered systemically. Dosing of betaxolol 0.25%, dorsolamide 2% and brimonidine 0.2% was one eye drop on every 12, 8 and 12 hours, respectively. Dosing of ginkgo biloba was in minimal effective clinical dose of 40 mg on every 8 hours, orally. Exclusion criteria were: allergies, cardiovascular diseases, corneal abnormalities, previous intraocular surgery, pregnancy, anticoagulation therapy and insufficiency of liver and kidneys. RESULTS The age and gander of patients are presented on Table. Table 1. Age, gender and eye. Group Age ( x ±SD) Male Female Right eye Left eye Betaksolol 63.3± Betaksolol+Ginkgo 67.2± Dorsolamide 65.8± Dorzolamide+Ginkgo 62.8± Brimonidine 60.8± Brimonidine+Ginkgo 63.0± Visual acuity improved only in patients treated with brimonidine monotherapy, from 0.9±0.11 (0 month) to 1.0±0.11 (18 month). A visual acuity decreased in patients who used betaxolol and gikgo from 0.84±0.24 (0 month) to 0.81±0.27 (18 month) (Table 2). 4

7 Table 2. Visual acuity and cup/disc (C/D) ratio in the beginning and at the end of follow-up period. Group Visual acuity [log] C/D [log] ( x ±SD) ( x ±SD) 0 month 18 month 0 month 18 month Betaksolol 0.86± ± ± ±0.23 Betaksolol+Ginkgo* 0.84± ± ± ±0.2* Dorsolamide 0.9± ± ± ±0.17 Dorsolamide+Ginkgo 0.95± ± ± ±0.24 Brimonidine* 0.9± ±0.11* 0.51± ±0.22 Brimonidine+Ginkgo 0.97± ± ± ±0.19 *p<0.05 (t-test). C/D ratio increased in patients who were treated with a combined therapy of betaxolol and ginkgo, from 0.57±0.23 (0 month) to 0.64±0.2 (18 month) (Table 2). A systolic and diastolic blood pressure decreased in both groups that used betaxolol. Combination of dorzolamide and ginkgo biloba decreased systolic blood pressure only (Table 3). Table 3. Systolic and diastolic blod pressure values in treated groups. Blood pressure ( x ±SD) Groups 0 month 6 month 18 month Systolic Diastolic Systolic Diastolic Systolic Diastolic Betaksolol** 136.9± ± ± ± ±26.1* 82.9±12.6* Betaksolol+Ginkgo** 145.2± ± ± ± ±22.0* 80.3±11.7* Dorsolamide 142.1± ± ± ± ± ±11.7 Dorsolamide ± ± ± ± ±19.0* 80.3±9.8 Ginkgo * Brimonidine 132.5± ± ± ± ± ±10.3 Brimonidine+Ginkgo 121.5± ± ± ± ± ±9.5 ** p<0.05 in both systolic and diastolic blood pressure. (ANOVA). 5

8 IOP decreased in all groups except in group with combined therapy of brimonidine and ginkgo in which IOP did not change. Local monotherapy showed greater IOP decrease than therapy combined with ginkgo (Tables 4-9). Table 4 and 5. IOP in Betaxolol groups. Betaxolol IOP [mmhg] ±SD Betaxolol+Ginkgo IOP [mmhg] ±SD Follow up [month] 8AM 12AM* Follow up [month] 8AM* 12AM 0* 14.7± ±1.6* 6* 14.5± ±2.1* ± ±2.0 18* 11.6± ±0.8* 0* 15.1± ±1.7* ± ± ± ±1.2 18* 12.1± ±1.4* t-test (*p<0.05). Table 6 and 7. IOP in Dorsolamide groups. Dorsolamide IOP [mmhg] ±SD Dorsolamide + Ginkgo IOP [mmhg] ±SD Follow up [month] 8AM* 12AM Follow up [month] 8AM* 12AM* 0* 16.1± ±2.1* ± ± ± ± ± ± ± ± ± ± ± ± ± ±2.6 t-test (*p<0.05). 6

9 Table 8 and 9. IOP in Brimonidine groups. Brimonidine IOP [mmhg] ±SD Brimonidine +Ginkgo IOP [mmhg] ±SD Follow up [month] 8AM* 12AM* Follow up [month] 8AM 12AM ± ± ± ± ± ± ± ± ± ± ± ± ± ±2.0 18* 14.4± ±3.4* t-test (*p<0.05). The increase in retina sensitivity was highest in both brimonidine groups although it was significant only in group treated with gingko as additional drug, from -7.94±5.9 db (0 month) to -6.17±6.5 db (18 month) (Table 10). Table 10. MD values throughout of 18 months follow-up period. Groups MD [db] ( x ±SD) Difference [db] 0 month 6 month 12 month 18 month 0/18 month Betaksolol -4.05± ± ± ± Betaksolol+Ginkgo -7.69± ± ± ± Dorsolamide -5.61± ± ± ± Dorsolamide ± ± ± ± Ginkgo Brimonidine -9.18± ± ± ± Brimonidine+ Ginkgo* *p<0.05 (ANOVA) ± ± ± ±6.5*

10 Improvement of PSD was found in patients treated with combined therapy of dorsolamide/ginkgo and brimonidine/ginkgo, 5.37±2.3 (0 month) to 3.86±2.3 (18 month) and 7.04±4.0 (0 month) to 5.99±4.2 (18 month) respectively (Table 11). Table 11. PSD values in investigated groups of patients. Groups PSD ( x ±SD) Difference 0 mesec 6 mesec 12 mesec 18 mesec 0/18 mesec Betaksolol 4.67± ± ± ± Betaksolol+Ginkgo 6.43± ± ± ± Dorsolamide 5.24± ± ± ± Dorsolamide+ 5.37± ± ± ±2.3* Ginkgo Brimonidine 6.49± ± ± ± Brimonidine+ Ginkgo* *p<0.05. (ANOVA) 7.04± ± ± ±4.2* In this study brimonidine induced most (28%) allergy reactions and this was predominantly ocular. No systemic side effects were registered with any of three investigated topical drugs or their combinations with ginkgo. 8

11 DISCUSSION A progression of perimetry defects in patients on glaucoma therapy are in range of -0.3 to db per year 18,19. A study of De Moares found average MD decrease of -0.7 db per year 20. The only group in this study with non significant decrease of MD value was betaxolol with gingko (-0.45 db per 18 months) and that rate was less than average comparing to value found by De Moares. Despite of IOP and blood pressure reduction, betaxolol with ginkgo also decrease visual acuity and increase of C/D ratio of optic nerve. This makes a combination of betaxolol with ginkgo inferior compared to other investigated drugs therapies for NTG.It also seems that IOP decrese is probably not the only factor responsible for retina ganglion cells preservation in NTG. An average decrease of IOP in betaxolol and dorsolamide groups was 20% and 10% respectively. A brimonidine monotherapy group had 15% IOP decrease. Contrary, brimonidine with ginkgo group showed 4.8% increase of IOP after 18 months of follow-up. An IOP lowering effect combined with same blood pressure lowering could lead to retina hypoperfusion in all groups except in brimonidine/ginkgo group. Brimonidine/ginkgo group had a different retina perfusion rate as a result of difference in key parameter IOP. The study did not show with certainty whether the ideal balance of IOP and diastolic blood pressure is responsible for improvement of retina sensibility in brimonidne/ginkgo group or there was a neuroprotective effect of brimonidine. Considering a different IOP fluctuations in both brimonidine groups and data that showed increase in retina sensibility in both groups, it is possible that the neuroprotective effect of brimonidine was responsible for such changes. Two brimonidine groups showed a highest retina sensitivity increase and have had a different fluctuation of IOP with no change in diastolic blood pressure. A side effects of brimonidine in this study had slightly higher rate than in other studies (Table 12). 9

12 Table 12. Side effects of brimonidine in other studies. Author/Follow-up period [months] Side effects [%] Katz/ Krupin/ Rahman/ Andreić (this study)/18 28 CONCLUSION Considering improvement of retinal sensitivity and no statistically significant change of IOP in NTG patients treated with combined therapy of brimonidine and ginkgo biloba, implies the neuroprotective effect of this combination of drugs. Brimonidine 0.2% eye drops in combination with ginkgo biloba administered systemically was superior compared to other investigated drugs therapies for NTG. 10

13 ACKNOWLEDGEMENTS There was no funding and(or) support for this research. Author have no conflicts of interest, including financial and (or) proprietary interests in this study. Author designed and conducted this study including collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. References: 1. European Glaucoma Society. Terminology and guidelines for glaucoma 3 rd edition. Savona, Italy, DOGMA, 2008: Michalk F, Michelson G, Harazny J, Werner U, Daniel WG, Werner D. Single-dose nimodipine normalizes impaired retinal circulation in normal tension glaucoma. J Glaucoma 2004;13(2): Mitchell P, Smith W, Attebo K, Healey PR. Prevalence of open angle glaucoma in Australia. The Blue Mauntains eye study. Ophthalmology 1996;103(10): Cheng JW, Cai JP, Wei RL. Meta-analysis of medical intervention for normal tension glaucoma. Ophthalmology 2009;116(7): Hickenbottom SL, Grotta J. Neuroprotective therapy. SeminNeurol 1998;18: Levin LA. Intrinsic survival mechanisms for retinal ganglion cells. Eur J Ophthalmol 1999;9:S Harris A, Spaeth GL, Sergott RC, Katz LJ, Cantor LB, Martin BJ. Retrobulbar arterial hemodynamic effects of betaxolol and timolol in normal-tension glaucoma. Am J Ophthalmol 1995;120(2): Ohtake Y, Tanino T, Kimura I, Mashima Y, Oguchi Y. Long-term efficacy and safety of combined topical antiglaucoma therapy - timolol&unoprostone vs. betaxolol&unoprostone. Nippon GankaGakkaiZasshi 2004;108(1):

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