Eye Drops, not as Innocent as they Seem: a Brief Review on Potential Adverse Effects of Ocular Therapy

To assess the impact of open versus masked adherence monitoring on adherence with topical brimonidine using two different dosing schedules. Thirty-seven patients with glaucoma or ocular hypertension were enrolled in a prospective, observational cohort study. Patients were randomly assigned to open or masked adherence monitoring and to brimonidine twice daily (BID) or three times daily (TID). Patients received conventional brimonidine eye drops with attached electronic monitoring devices for 4 weeks with weekly intraocular pressure measurements. Adherence calculations comprised dosing intervals, adherence rate and time covered. Subgroup analysis with anova included the factors masking, regimen, diagnosis and age. Among 36 individually analysed patients, 12 (33%) had adherence rates above 75%, therein two (5%)>90%. The mean adherence rate in 19 patients aware of adherence measurements was 70 ± 17% for brimonidine BID and 65 ± 14% for TID, not significantly different to the rates of 17 patients not informed about adherence measurements (77 ± 6% BID, 62 ± 9% TID, p = 0.24). On average, patients with brimonidine TID achieved significantly lower adherence rates (64 ± 12%) than patients on BID (73 ± 13%, p = 0.02). Still, patients on TID applied brimonidine more often (TID 1.9 ± 0.3, BID 1.5 ± 0.1 mean applications per day). The median coverage was 70% and showed no statistically significant difference between patients on BID and TID (p = 0.36). The study findings suggest that adherence measurements are not significantly altered by open adherence monitoring, which may simplify future adherence studies. Adherence with brimonidine eye drops was insufficient for most patients. These results demonstrate the necessity to develop new strategies to improve compliance in glaucoma therapy.

ObjectivesTo investigate the use of autologous serum (AS) eye drops in patients with ocular surface disorders who were refractory to conventional treatments.MethodsA retrospective cohort study was conducted at a tertiary...

Background: Ocular component is the most prominent and disabling feature of allergy leading to symptoms like itching and watering of eyes causing significant irritation. Allergic conjunctivitis (AC) is one of the most common ocular conditions affecting adult and pediatric patients that requires treatment by ophthalmologists. AC and its debilitating symptoms like itching, watering of eyes and ropy discharge have interfered their day to day activities, difficulty in concentrating in work and has adversely affect the quality of life. Aim and objectives were to study and compare the efficacy and safety profile of topical alcaftadine versus topical o lopatadine eye drops in patient with AC. To compare efficacy of topical alcaftadine versus topical olopatadine eye drops, to observe adverse drug reaction of both eye drops. Methods: A prospective, open labelled comparative hospital based study was conducted in the department of ophthalmology in collaboration with department of pharmacology GMC Haldwani, Uttarakhand. Patients with AC (n=120) were randomised into two groups: Alcaftadine 0.25% eye drop and olopatadine 0.2% eye drop once daily. Patients were assessed on the first day 2nd week and 4th week. Reduction in total severity score and efficacy was measured in both treatment groups. Safety was assessed by observing adverse drug reaction using WHO UMC Causality assessment scale and modified Hartwig Siegel’s severity scale. Results: A trend in significant improvement in patients treated with alcaftadine eye drop in comparison to patients treated with olopatadine eye drop at both second week and fourth week follow up. No adverse effects were reported with either eye drops in both groups. Conclusions: Alcaftadine eye drop showed higher efficacy than olopatadine eye drop in relieving signs and symptoms of AC. Both treatment groups were found to be safe and effective.

Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence-based treatment is a lowering of IOP through the use of eye drops, laser procedures, or surgical interventions. Although laser treatment is gaining recognition as a first-choice treatment option, the most common approach for managing glaucoma is IOP-lowering eye drops. A major challenge in the treatment is the occurrence of adverse events and poor adherence. In this context, the ocular surface is an area of great concern, as most glaucoma patients have dry eye disease (DED), which is largely caused by eye drops. Preservation with benzalkonium chloride (BAK) is a controversial topic due to its potential role as a significant cause of DED. A systematic review and meta-analyses investigate potential differences in efficacy and safety between BAK-preserved and BAK-free anti-glaucomatous eye drops (I). Many of the included studies report on ocular surface damage caused by the application of BAK-preserved eye drops. However, the meta-analyses addressing hyperemia, number of ocular adverse events, and tear break-up time did not identify any significant differences. The latter is likely due to varying measurement methods, different endpoints, and study durations. It is, therefore, possible that the large variations between the studies conceal differences in the safety profiles. The efficacy meta-analysis finds that there are no differences in the IOP-lowering effect between BAK-preserved and BAK-free eye drops, indicating that BAK is not necessary for the effectiveness of eye drops. To promote more homogeneous choices of endpoints and methods when evaluating BAK-preserved and BAK-free glaucoma treatments, a Delphi consensus statement was performed. In this study, glaucoma experts and ocular surface disease experts reached consensus on the key factors to consider when designing such studies (II). The hope is to have more studies with comparable endpoints that can systematically show the potentially adverse effects of BAK. The preclinical studies in the current Ph.D. research focus on conjunctival goblet cells (GCs). GCs are important for the ocular surface because they release the mucin MUC5AC, which is an essential component of the inner layer of the tear film. BAK preservation may damage the GCs and result in a low GC density, leading to an unstable tear film and DED. The most commonly used IOP-lowering drugs are prostaglandin analogs (PGAs). Thus, the conducted studies investigate the effect of PGAs preserved in different ways on GCs. BAK-preserved latanoprost is cytotoxic to primary cultured human conjunctival GCs and results in a scattered expression of MUC5AC, in contrast to negative controls, where MUC5AC is localized around the cell nucleus (III). Preservative-free (PF) latanoprost is not cytotoxic and does not affect the MUC5AC expression pattern. Furthermore, BAK-preserved travoprost is found to be cytotoxic in a time-dependent manner, while Polyquad®-preserved travoprost does not affect GC survival at any measured time point (IV). Both Polyquad and BAK induce scattered expression of MUC5AC. The cytotoxicity of BAK-preserved PGA eye drops is higher compared to the safer profile of PF and Polyquad-preserved PGA eye drops (V). Additionally, PF latanoprost does not increase the release of the inflammatory markers interleukin (IL)-6 and IL-8, unlike BAK-preserved latanoprost. A review highlights the active and inactive components of IOP-lowering eye drops (VI). Several preclinical and clinical studies have identified adverse effects of BAK. Although other components, such as the active drug and phosphates, can also cause adverse events, the review clearly states that BAK alone is a major source of decreased tolerability. The conclusion of this thesis is that BAK preservation is unnecessary and harmful to the ocular surface. The preclinical studies demonstrate that GCs die when exposed to BAK. Furthermore, they find that BAK induces a pro-inflammatory response. The review included in the thesis concludes that BAK should be phased out of eye drops for chronic use. Overall, the inclusion of BAK poses a risk of developing DED and poor adherence, which can ultimately lead to disease progression and blindness.

Re: Zander et al.: Hyperosmolar eye drops for diurnal corneal edema in Fuchs’ endothelial dystrophy: a double-masked randomized controlled trial (Ophthalmology. 2021;128:1527–1533)

Many patients are treated for glaucoma. Like other drugs, anti-glaucoma eye drops may induce dermatological adverse effects. We aim to review the dermatological adverse effects secondary to the active agents in anti-glaucoma eye drops through a literature review. In January 2020, we queried PubMed using the following MeSH terms: glaucoma/drug therapy or glaucoma, open angle/drug therapy cross-referenced with parasympathomimetics/adverse effects or adrenergic agonists/adverse effects or carbonic anhydrase inhibitors/adverse effects or prostaglandins F, synthetic/adverse effects or adrenergic beta antagonists/adverse effects or ophthalmic solutions/adverse effects. The initial search identified 1128 studies, of which 49 were excluded for being in a foreign language, 15 for not involving eye drops, 968 for not focusing on adverse dermatological effects, and 11 for insufficient documentation or redundancy. After adding 38 linked studies, we finally analyzed 123 studies. The ocular and periocular dermatological adverse effects of eye drops are contact dermatitis, hyperpigmentation, prostaglandin analog periorbitopathy, mucous membrane pemphigoid, eyelash depigmentation, skin hypertrichosis, and rare cases of melanoma and skin depigmentation. The reported distant dermatological adverse effects are psoriasis, excessive sweating, lichen planus, alopecia, toxic epidermal necrolysis, erythema multiforme, erythroderma, subacute cutaneous lupus erythematosus, nail pigmentation, and bullous pemphigoid. Most of the cutaneous adverse effects of anti-glaucoma eye drops are ocular and periocular and induced by prostaglandin analogs. Distant adverse effects are rare and sometimes questionable but should be kept in mind, especially mucous membrane pemphigoid, which could lead to blindness. The role of preservatives, such as benzalkonium chloride, should also be considered.

Objective To investigate the efficacy and safety of 0.15％ brimonidine tartrate (Alphagan P)eye drops.Methods 86 eyes of 46 cases with primary open angle glaucoma (POAG) or ocular hypertension were dosed with Alphagan P eye drops alone or as an adjunctive therapy as one drop a time,thrice daily.The intraocular pressure (IOP) at 2,4,8 and 12 weeks after sustained instilling were compared with the baseline.On the other hand,systematic and local adverse effects were also observed.Results Alphagan P eye drops reduced IOP significantly.The mean IOP decreased from the baseline (22.89 ±3.91)mmHg(1 mmHg =0.133 kPa) to(19.43 ±2.84),(19.43 ±3.44),(18.98 ±3.17)and (18.87 ± 2.83)mmHg at 2,4,8 and 12 weeks after sustained instilling respectively.There were statistical differences between baseline and the IOP at four time points (P ＜ 0.01).No matter dropped Alphagan P alone or taken it as an adjunctive therapy or switched to Alphagan P during trentment,there were statistical differences between baseline and the IOP at four time points after sustained instilling (P ＜ 0.01).The major adverse effects didn' t affect continuous medication.Conclusion Alphagan P eye drops can reduce IOP significantly in the patients with POAG or ocular hypertension.It is safe and effective. Key words: Eye drops, brimonidine tartrate, 0.15％ ; Eye drops, Alphagan P; Glaucoma

Purpose: To compare two gel-forming timolol maleate ophthalmic solutions, Timoptol XE^® and Lizmon TG^®, in regard to efficacy and tolerability in patients with glaucoma or ocular hypertension by means of a patient-masked prospective randomized crossover study. Subjects and Methods: A total of 37 patients with glaucoma or ocular hypertension under treatment with antiglaucoma ophthalmic solutions including 0.5% twice-daily timolol maleate participated in this study. Only timolol maleate was withdrawn and either Timoptol XE or Lizmon TG was randomly allocated. After instillation for 1 month, the other ophthalmic solution was subsequently instilled for another month. Routine ophthalmic examination including slit-lamp examination and intraocular pressure (IOP) monitoring was conducted before instillation of gel-forming ophthalmic solutions and just after completing the instillation of each ophthalmic solution. Patient questionnaire surveys were also performed just after completing the instillation of each ophthalmic solution. Results: Mean IOP, just before the withdrawal of timolol ophthalmic solution, was 16.4 ± 2.9 mm Hg. At the end of Timoptol XE or Lizmon TG instillation, mean IOPs were 16.3 ± 2.5 or 16.3 ± 3.0 mm Hg, respectively. The results of the questionnaire survey showed no significant difference between Timoptol XE and Lizmon TG in regard to all survey items. Twenty-nine patients (78.4%) preferred to use gel-forming timolol solutions rather than twice-daily timolol ophthalmic solution. The presence of concurrently used ophthalmic solutions did not effect the incidences of subjective symptoms. The incidences of objective adverse effects were not significantly different between two gel-forming timolol ophthalmic solutions. Conclusion: Both gel-forming timolol ophthalmic solutions could be good choices for glaucoma treatment.

Background Nd: YAG laser posterior capsulotomy is an important way for after cataract.Usually the patient will use glucocorticoid eye drops to treat the anterior chamber inflammation after operation,but there is potential risk of elevating intraocular pressure (IOP).Objective This study was to compare the clinical effectiveness and safety of loteprednol etabonate ophthalmic suspension,tobramycin+ dexamethasone eye drops and fluorometholone eye drops following Nd: YAG laser posterior capsulotomy.Methods A randomized-controlled clinical trail was performed.One hundrcd and seventy-onc cycs of 127 paticnts who received Nd: YAG laser posterior capsulotomy for after cataract were randomly divided into four groups.Loteprednol etabonate ophthalmic suspension,fluorometholone eye drops,tobramycin+dexamethasone eye drops and systane eye drops was topically administered respectively in the four groups after laser posterior capsulotomy and 6 times per day for 5 days.IOP was measured with Goldmann tomometer 1 hour before operation and 1 hour,1 day,3 days and 7 days after operation.The ocular anterior segment inflammatory response was examined under the slit lamp and scored based on the Peizeng criteria.Written informed consent was obtained from each patient before any relevant medical procedure.Results The IOP was (18.2 ±4.7),(20.1 ±5.7),(18.7±5.5),(19.0 ±4.1),(19.5 ±3.5) mmHg in various time points in the loteprednol etabonate group; (18.7 ±5.3),(20.9±5.7),(21.3±4.5),(21.0±4.9),(22.5±6.5) mmHg in the fluorometholone eye drops group ; (17.9± 6.3),(20.3 ± 6.1),(23.0 ± 3.7),(24.7 ± 4.9),(24.5 ± 6.5) mmHg in the tobramycin +dexamethasone group and(18.4±6.3),(20.7±3.7),(22.7±6.5),(19.6±4.8),(18.5±3.5) mmHg in the systane group,showing a significant difference among the 4 groups (Fgroup =3.876,P =0.023).With the time lapse,the IOP was gradually reduced in the loteprednol etabonate group and systane group,but that in the fluorometholone group and tobramycin+dexamethasone group was elevated,showing a significant difference among them (Ftime =3.801,P =0.031).No any ocular and systemic adverse effect was found in various groups.The percentage of grade 1 and 2 of aqueous inflammatory cells was lower in the loteprednol etabonate group and tobramycin+dexamethasone group than the fluorometholone group and fluorometholone group and systane group(H =8.276,P =0.012).The percentage of Ⅰgrade of aqueous flare was 8％ in the loteprednol etabonate group,22％ in the fluorometholone group,18％ in the tobramycin+dexamethasone group and 30％ in the systane group,with a significant difference among them (H=9.305,P=0.000).Conclusions The use of corticosteroid eye drops can relieve the inflammatory response of ocular anterior chamber after Nd: YAG laser posterior capsulotomy.Loteprednol etabonate ophthalmic suspension has a better anti-inflammatory effect and less influence on IOP. Key words: Nd : YAG laser; After cataract; Posterior capsulotomy; Loteprednol etabonate; Glucocorticoid; Intraocular pressure

Glaucoma is a chronic, progressive disease in which retinal ganglion cells disappear and subsequent, gradual reductions in the visual field ensues. Glaucoma eye drops have hypotensive effects and like all other medications are associated with adverse effects. Adverse reactions may either result from the main agent or from preservatives used in the drug vehicle. The preservative benzalkonium chloride, is one such compound that causes frequent adverse reactions such as superficial punctate keratitis, corneal erosion, conjunctival allergy, and conjunctival injection. Adverse reactions related to main hypotensive agents have been divided into those affecting the eye and those affecting the entire body. In particular, β-blockers frequently cause systematic adverse reactions, including bradycardia, decrease in blood pressure, irregular pulse and asthma attacks. Prostaglandin analogs have distinctive local adverse reactions, including eyelash bristling/lengthening, eyelid pigmentation, iris pigmentation, and upper eyelid deepening. No systemic adverse reactions have been linked to prostaglandin analog eye drop usage. These adverse reactions may be minimized when they are detected early and prevented by reducing the number of different eye drops used (via fixed combination eye drops), reducing the number of times eye drops are administered, using benzalkonium chloride-free eye drops, using lower concentration eye drops, and providing proper drop instillation training. Additionally, a one-time topical medication can be given to patients to allow observation of any adverse reactions, thereafter the preparation of a topical medication with the fewest known adverse reactions can be prescribed. This does require precise patient monitoring and inquiries about patient symptoms following medication use.

To investigate the effect of differently preserved ophthalmic solutions on the viability and barrier function of human corneal epithelial cells (HCEC) using fluorescent dyes. HCEC monolayers were exposed to the ophthalmic solutions containing benzalkonium chloride (BAK), edetate disodium, polyquad, stabilized oxychloro complex (Purite), sodium perborate, or sorbic acid for 5 min, 15 min, and 1 h. At 24 h after exposure, the cultures were assessed for metabolic activity using alamarBlue. The enzyme activity, membrane integrity, and apoptosis were evaluated using confocal microscopy. Barrier function was assessed using sodium fluorescein. The metabolic assay showed that the BAK-preserved ophthalmic solutions significantly reduced cell viability after a 5-min exposure compared to the phosphate buffered saline treated control (P<0.05). Using confocal microscopy, the micrographs showed that BAK caused a reduction in the enzyme activity, increased membrane permeability, and decreased the number of viable cells. Ophthalmic solutions with new preservatives had varying time-dependent adverse effects on cell viability, and the preservative-free solution had the least effect on HCEC. Sodium fluorescein permeability showed that HCEC monolayers treated with BAK-preserved solutions were more permeable to sodium fluorescein than those treated by the other ophthalmic solutions (P<0.05). BAK-preserved solutions had greater adverse effects on metabolic activity, enzyme activity, membrane integrity, cell viability, and barrier function than the solutions that were not preserved with BAK. Our study suggests that BAK-free especially, preservative-free ophthalmic solutions are safer alternatives to BAK-preserved ones.

Objective: Although allergic conjunctivitis seldom causes visual impairment, it holds significance due to its frequency and severity. This study was carried out to compare the safety and efficacy of Alcaftadine 0.25% and Olapatadine 0.2% ophthalmic solutions in treating the symptoms and signs of allergic conjunctivitis as there is not much literature comparing these two drugs directly. Materials and methods: This is a prospective, observer masked study of 80 patients with allergic conjunctivitis assigned to two groups-Group I: 40 patients received Alcaftadine 0.25% and Group II:40 patients received Olapatadine 0.2% ophthalmic solution and relief of symptoms were noted and assessed with a follow at 1 week and 1 month. Results: Eyes treated with Alcaftadine 0.25% had significantly low mean itch score of 0.6 compared to Olapatadine 0.2% ophthalmic solution which was 1. Eyes treated with both Alcaftadine 0.25% and Olapatadine 0.2% ophthalmic solutions reduced lid swelling, redness and discharge; safe and no serious adverse effects were encountered. Conclusion: BothAlcaftadine 0.25% and Olapatadine 0.2% ophthalmic solutions used in the study are safe and effective in treating the symptoms and signs of Allergic conjunctivitis. However, Alcaftadine 0.25% ophthalmic solution is comparatively more efficacious.

Acute onset comitant esotropia associated with spasm of accommodation in children and adults is a rare clinical condition. When occurring with pupillary miosis and restricted ocular motility, it is referred to as "spasm of near reflex" (SNR) and may require neurological investigation. The natural history of SNR depends on its etiology. There is little information in the literature regarding the long-term follow-up of SNR and the stability of visual signs and symptoms following cessation of treatment. We report a case of SNR in an otherwise healthy young male, and discuss the presentation, clinical investigations, management, response to treatment, and 1-year follow-up. A 23-year-old male patient reported to the clinic with sudden onset of blurred vision, inward deviation of the eyes, and binocular diplopia. On examination, he was diagnosed to have acute onset esotropia resulting from SNR. He was treated with cycloplegic medications and vision therapy. The condition resolved following 1 year and there has been no recurrence. Acute adult onset esotropia occurring with accommodative spasm responds favorably to cycloplegic medications but may need a longer course of treatment for successful resolution and stability.

Préparation d’un collyre de ciclosporine à 2 %

Glaucoma is the condition where the intraocular pressure of the eyeball increases more than normal.There are mainly two types of glaucoma 1 . Primary open angle glaucoma, 2. Primary angle closure glaucoma Population affected with primary open angle glaucoma is large. Treatment includes alpha selective adrenergic agents, sympatholytic agents and other drugs. The most commonly used drugs in the Govt General Hospital, Vijayawada, A.P were sympatholytic agents and alpha selective adrenergic drugs .So we carried out the study comparing the efficacy cost effectiveness and adverse drug reactions between timolol 0.5% eye drops and brimonidine tartarate 0.2% eye drops in primary open angle glaucoma. It was a comparative, randomized, prospective study .100 patients were recruited and they were randomly divided in group A and group B.Group A was given timolol 0.5% eye drops and group B was given brimonidine tartarate 0.2% eye drops.The patients were observed during 1 st week ,2 nd week ,4 th week ,8 th week,12 th week,16 th ,20 th and 24 th week .In the early weeks, Brimonidine tartarate effectively decreased intraocular pressure but in the later weeks timolol reduced more effectively than brimonidine.'P' value was significant. Timolol was cheaper than brimonidine and adverse effects were also less. So, it was concluded that timolol was most effective both in reducing the symptoms and in cost effectiveness when compared to brimonidine in the management of primary open angle glaucoma. Adverse effects were also less for timolol .So it was a better drug in the management if primary open angle glaucoma when compared to brimonidine.