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Purpose: This study investigates brimonidine's potential effect on visual functions, particularly contrast sensitivity (CS), an indicator of retinal ganglion cell function., Methods: In this single-blind, randomized clinical trial, 60 patients (aged 23-56) with first-episode acute optic neuritis within seven days of symptom onset were randomly assigned to brimonidine or control groups. The intervention group received brimonidine three times daily for three months, while the control group received synthetic tears with the same dosage and frequency. Primary outcomes were changes in CS, visual acuity (VA), and color vision at one and three months post-treatment. Repeated measures ANOVA was used to assess statistically significant and partial eta squared (η2) values, mean differences, and clinically significance important were reported., Results: All participants completed the study without complications. VA improved significantly in both groups by follow-up end (p < 0.001), with significant improvement from first to third month only in the brimonidine group (p < 0.001). The mean VA difference between groups was not statistically and clinically significant. CS showed statistically significant improvement within both groups (p < 0.001) and between groups (p < 0.001), with a large effect size (partial η2 = 0.28). The mean CS difference between groups (14.5) was clinically considerable. No significant changes in color vision were observed between groups (p = 0.96)., Conclusion: Brimonidine significantly improved contrast sensitivity compared to placebo and was well-tolerated. Its neuroprotective effects suggest it may be beneficial in treating optic neuritis and preserving retinal ganglion cell function., Trial Registration: Prospectively registered at Iranian Clinical Trial Registration; Registration date 3 December 2022; Registration number: IRCT20221127056631N1., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The hen's egg test on chorioallantoic membrane (HET-CAM) assay is a cost-effective and well-validated, non-animal-based ex vivo method for evaluating the irritant potential and eye toxicity of substances. A colloidal dispersion of a surfactant and a cosurfactant with a nanosize range is called a nanoemulsion (NE), which is formed by mixing immiscible liquids and stabilized by surfactants. Patients with glaucoma are commonly prescribed Brimonidine (BR), an alpha-2 adrenergic agonist, to lower their intraocular pressure., Materials and Methods: In this study, surfactant-cosurfactant blends were prepared by mixing Tween 80 (surfactant) and propylene glycol (cosurfactant) in a 4:1(v/v) ratio. Triacetin served as the oil phase, while deionized water was used as the aqueous phase. Using the drop method, a range of NE formulations (F1, F2, F3, FB1, FB2, and FB3) were developed and subsequently evaluated for their potential to irritate, and then the results were compared to those of a commercially available BR eye drop formulation., Results: According to the average cumulative HET-CAM test scores (IS), from excipients, propylene glycol caused moderate irritation by causing slight damage to blood vessels. The formulations FB1 and F1 were found to have the highest level of irritation among other formulations in the investigation, recording 1.05 ±0.07 and 1.2 ±0.10, respectively. All other NE formulations exhibited non-irritating potential, as confirmed by the HET-CAM test, and were comparable to the marketed BR eye drop formulation., Conclusion: The NE formulations created for BR were determined to be safe and non-irritating. The findings indicate that the prepared NE could be a beneficial solution for addressing problems with conventional eye drops and delivering BR effectively to the eyes., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Smail et al.)

Objectives : The purpose of this study was to investigate switching from brimonidine and ripasudil, and brimonidine or ripasudil, to a fixed combination of brimonidine and ripasudil, and evaluate the associated efficacy and safety in glaucoma patients. Methods : Glaucoma patients undergoing treatment with at least brimonidine and ripasudil (n = 25) or treatment with at least brimonidine or ripasudil (n = 45) were evaluated in this retrospective study. After switching patients taking brimonidine and ripasudil, or brimonidine or ripasudil, to a ripasudil/brimonidine fixed-combination, ophthalmic suspension (RBFC), intra-ocular pressure (IOP), conjunctival hyperemia and superficial punctate keratopathy (SPK) were evaluated before and at 4, 12 and 24 weeks after switching to RBFC. Results : No significant differences in the IOPs were observed after switching from brimonidine and ripasudil to RBFC. However, a significant decrease was observed at 4, 12 and 24 weeks in the baseline IOP, from 17.0 ± 4.4 mmHg to 15.7 ± 3.2 mmHg ( p < 0.01), 14.3 ± 3.4 mmHg ( p < 0.01) and 14.4 ± 4.1 mmHg ( p < 0.01), respectively, after switching from brimonidine or ripasudil to RBFC. No significant changes were noted for the SPK score or conjunctival hyperemia score at any of the visits after switching to RBFC. Conclusions : Throughout the 24-week evaluation period, the IOP was maintained after switching from brimonidine and ripasudil to RBFC. However, there was a significant decrease in the IOP after switching from brimonidine or ripasudil to RBFC. These results demonstrate that RBFC is safe for use in the treatment of glaucoma patients.

Background: Bradycardia can have a number of different aetiologies, including as a side effect of medications. Brimonidine is a rare, but recognized, cause of bradycardia. Brimonidine is indicated in the treatment of facial erythema in rosacea when given as topical brimonidine gel (Mirvaso). It may also be administered as eye drops for raised intraocular pressure in open-angle glaucoma and ocular hypertension. Brimonidine is an alpha-2 agonist, which if systemically absorbed can present with bradycardia, hypotension, and dizziness. The authors are unaware of any other case reports regarding topical administration of Mirvaso in an adult and symptomatic bradycardia., Case Summary: We present the case of a 78-year-old man with a background of rosacea, benign prostatic hyperplasia, and hypertension who had two separate admissions with symptomatic bradycardia. Electrocardiograms showed sinus bradycardia with AV block first degree, with rate recorded as low as 31 b.p.m. during a syncopal episode. These episodes of symptomatic bradycardia were intermittent and had a temporal association with topical administration of Mirvaso. He had no further episodes of bradycardia on discontinuation of Mirvaso and has remained symptom free for over 6 months., Discussion: The topical administration of Mirvaso should be avoided to broken or inflamed skin. This is owing to the increased risk of systemic absorption, which as in this case report, may present with bradycardia. This case reiterates the importance of completing a full medication history including all topical and parenteral medications in patients with arrhythmia., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: To study the effect of brimonidine on vascular density and flow index of optic nerve head (ONH) and macula in primary open angle glaucoma (POAG) using optical coherence tomography angiography (OCTA)., Methods: Twenty-three brimonidine-naïve POAG patients were started on brimonidine. They underwent OCTA ONH and macula before commencing brimonidine and one month thereafter. Systemic arterial blood pressure (SABP) and intraocular pressure (IOP) were measured at each visit to calculate mean ocular perfusion pressure (MOPP). The OCT angiograms were analyzed using ImageJ software to calculate ONH and macular flow indices., Results: Thirty-seven eyes (23 patients) with a mean age of 56.7 ± 12.49 years were included of whom 60.8% were males. Brimonidine was associated with an increase in the superficial flow index (SFI) (P-value = 0.02) and optic nerve head flow index (ONHFI) (P-value = 0.01). Also, superficial vascular density (SVD) for whole image, superior-hemi and fovea increased (P-value = 0.03, 0.02, 0.03 respectively). ONH inferior-hemi vascular density decreased (P-value = 0.01) despite an increase in inferior quadrant retinal nerve fiber layer thickness (RNFLT) (P-value = 0.03). There was no statistically significant correlation between flow indices and MOPP at baseline and follow-up. A moderate negative correlation was found between SVD and DVD at the fovea and MOPP at baseline and follow-up (P-value = 0.03, 0.05) (P-value = 0.02, 0.01) respectively., Conclusions: Brimonidine was associated with an increase in SFI, ONHFI and SVD indicating improved GCC and RNFL perfusion in POAG. Despite the increase in inferior quadrant RNFLT, the concomitant decrease in inferior-hemi ONHVD precluded a conclusion of hemodynamically-mediated improvement of RNFLT., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

In this study, we report paracentral acute middle maculopathy (PAMM) and cotton wool spots (CWS) in a patient with ocular migraine. A 74-year-old man presented with persistent paracentral scotoma in the right eye that began a week prior. His visual acuity was 20/25 in the right eye and 20/40 in the left. Dilated fundoscopy revealed CWS in the right eye. Spectral-domain optical coherence tomography (SD-OCT) showed hyper-reflective bands in the inner nuclear layer corresponding to parafoveal lesions seen on near-infrared imaging in the right eye consistent with the diagnosis of PAMM. Further laboratory studies were unremarkable, and a transthoracic echocardiogram and a carotid ultrasound were unrevealing. The patient was started on brimonidine three times daily in both eyes. The patient reported subjective improvement in the paracentral scotoma and the absence of ocular migraine symptoms at two-month follow-up. We conclude from this case that PAMM and CWS can occur simultaneously in ocular migraine, and we suggest that retinal vascular changes associated with ocular migraine may contribute to ischemia underlying both entities. Additionally, we suggest a potential therapy in brimonidine due to its proposed beneficial effects on retinal vasculature and neuroprotection., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background/aim: Diabetic retinopathy is a leading cause of blindness worldwide, characterized by neurovascular dysfunction. This study aimed to investigate the impact of brimonidine, a selective adrenoceptor agonist, on diabetic retinal neurodegeneration, recognizing the critical role of neurodegeneration in diabetic retinopathy., Materials and Methods: Streptozotocin-induced diabetes was established in adult male Sprague-Dawley rats to mimic diabetic retinopathy. Rats, except non-diabetic control rats, received topical applications of 0.15% brimonidine tartrate (treatment group) or balanced salt solution (diabetic control group) twice daily following diabetes induction. Each group comprised six randomly assigned animals. Retinal samples were analyzed using immunofluorescence staining, apoptosis assay, and western blot., Results: Topical brimonidine treatment reduced apoptosis of retinal ganglion cells at 8 weeks after induction of diabetes (p<0.05). Glial activation induced by diabetes was reduced by brimonidine treatment. Immunoblot and immunofluorescence assay revealed that the decrease in phospho- protein kinase B (AKT) level resulting from diabetes was also attenuated by brimonidine (p<0.05). Furthermore, brimonidine alleviated the decrease in anti-apoptotic proteins [BCL2 apoptosis regulator (BCL2) and BCL-xl] induced by diabetes (p<0.05). Elevation of phospho-p38 mitogen-activated protein kinase (p38MAPK) and p53 in diabetic rats were reduced by brimonidine (p<0.05). Additionally, brimonidine treatment attenuated the upregulation of the pro-apoptotic molecule BCL-2 associated X in retinas of diabetic rats (p<0.05)., Conclusion: These findings suggest that topical brimonidine treatment may protect retinal ganglion cells in experimental diabetes by modulating the AKT pathway and reducing pro-apoptotic p38MAPK levels. This presents a potential neuroprotective approach in diabetes, offering the advantage of localized treatment without the added burden of oral medication., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Glaucoma is one of the major irreversible blinding eye diseases in the world. Reducing intraocular pressure (IOP) is the primary treatment option, and taking eye drops daily is the common method. However, short drug duration and poor bioavailability of eye drops may lead to unsatisfied therapeutic effects and inadequate patient compliance., Methods: A brimonidine-loaded silicone rubber insert (BRI@SR@PT) was prepared by loading brimonidine into a surface-modified silicone rubber ring, followed by polydopamine/thermoplastic polyurethane coatings. The physical properties, in vitro cytocompatibility and drug release of BRI@SR@PT were investigated. The BRI@SR@PT was administrated in the conjunctival sac of rabbit eyes, and its in vivo drug release, IOP-lowering efficacy and biosafety were assessed., Results: The BRI@SR@PT presented great thermal stability and excellent elasticity. The BRI@SR@PT was able to release BRI sustainably for 28 days with little toxicity in vitro . Compared to BRI eye drops, the BRI@SR@PT effectively lowered IOP for 21 days based on the sustained BRI release with great biosafety when administrated in conjunctival sac of rabbit eyes in a noninvasive fashion., Conclusions: The conjunctival sac insert (BRI@SR@PT), as a promising drug-delivery platform, may provide a sustained IOP-lowering treatment for patients with ocular hypertension or glaucoma, without the need for invasive procedures.

Background: Myopia is becoming a huge burden on the world's public health systems. The purpose of this study was to explore the effect of brimonidine in the treatment of form-deprivation myopia (FDM) and the relationship between intraocular pressure (IOP) and myopia development., Methods: Monocular form deprivation myopia (FDM) was induced in three-week-old pigmented male guinea pigs. They were treated with 3 different methods of brimonidine administration (eye drops, and subconjunctival or intravitreal injections). Four different concentrations of brimonidine were tested for each method (2µg/µL, 4µg/µL, 20µg/µL, and 40µg/µL). All treatments continued for a period of 21 days. Tonometry, retinoscopy, and A-scan ultrasonography were used to monitor intraocular pressure, refractive error and axial length (AL), respectively., Results: Treatment with subconjunctival brimonidine at 40µg/µL, and intravitreal brimonidine at 2µg/µL and 4µg/µL, inhibited the development of FDM. The myopic refraction, excessive axial length, and elevation of IOP were significantly decreased. Brimonidine in eye drops was ineffective., Conclusion: Brimonidine at appropriate doses significantly reduced the development of FD myopia in guinea pigs. The IOP may change with FD myopia., (© 2024. The Author(s).)

Purpose: The ROCK inhibitor ripasudil hydrochloride hydrate was shown to have axonal protective effects in TNF-induced optic nerve degeneration. The α2-adrenoreceptor agonist brimonidine was also shown to exert axonal protection. The current study aimed to elucidate whether additive axonal protection was achieved by the simultaneous injection of ripasudil and brimonidine and examine the association with AMPK activation., Methods: Intravitreal administration was performed in the following groups: PBS, TNF, or TNF with ripasudil, with brimonidine, or with a combination of ripasudil and brimonidine. Axon numbers were counted to evaluate the effects against axon loss. Immunoblot analysis was performed to examine phosphorylated AMPK expression in optic nerves, and immunohistochemical analysis was performed to evaluate the expression levels of p-AMPK and neurofilament in the optic nerve., Results: Both ripasudil alone or brimonidine alone resulted in significant neuroprotection against TNF-induced axon loss. The combination of ripasudil and brimonidine showed additive protective effects. Combined ripasudil and brimonidine plus TNF significantly upregulated p-AMPK levels in the optic nerve compared with the TNF groups. Immunohistochemical analysis revealed that p-AMPK is present in axons and enhanced by combination therapy., Conclusion: The combination of ripasudil and brimonidine may have additive protective effects compared with single-agent treatment alone. These protective effects may be at least partially associated with AMPK activation., (© 2024. The Author(s).)

Background: This case report is applicable to the field of ophthalmology because there is a paucity of medical literature related to the clinical presentation, diagnosis, and management of uveal effusion syndrome. This is an urgent concern because there are severe complications associated with this disease, including non-rhegmatogenous retinal detachment, angle closure glaucoma, and possible blindness. This report will fill clinical knowledge gaps using a patient example., Case Presentation: A 68-year-old white male with multiple cardiovascular risk factors initially presented to the Eye Institute Urgent Care Clinic with new onset visual symptoms, including eye pain, eye lid swelling, redness, and tearing of his left eye. He had experienced a foreign body sensation in the left eye and bilateral floaters weeks prior to his presentation. The patient was examined, and vision was 20/30 in both eyes, and intraocular pressure was 46 in the right eye and 36 in the left eye. After initial assessment, including compression gonioscopy, intermittent angle closure glaucoma was suspected. He received oral diamox 500 mg, one drop of alphagan in both eyes, one drop of latanoprost in both eyes, one drop of dorzolamide in both eyes, and one drop of 2% pilocarpine in both eyes. There was only slight response in intraocular pressure. Owing to the bilateral angle closure, he underwent laser peripheral iridotomy to decrease intraocular pressure and open the angle that was found closed on gonioscopy. The patient was discharged on oral and topical glaucoma drops and scheduled for the glaucoma clinic. When he presented for follow-up in the glaucoma clinic, he was evaluated and noted to have bilateral narrow angles and intraocular pressure in the mid-twenties. A brightness scan (B-scan) was performed and was noted to have bilateral choroidal effusions, confirmed by Optos fundus photos. He was started on prednisone at 60 mg once per day (QD) with taper, continuation of oral and topical glaucoma medications, and a retina evaluation. Evaluation with a retina specialist showed resolving choroidal effusion in the left eye. He continued the prednisone taper as well as glaucoma drops as prescribed. Follow-up in the glaucoma clinic revealed a grade 3 open angle. He continued the prednisone taper, cosopt twice per day in both eyes, and discontinued brimonidine. The magnetic resonance imaging (MRI) that was performed showed results that were remarkable. No hemorrhage or mass was present. Follow-up with the retina specialist found that the choroidal effusions had resolved completely., Conclusion: This case report emphasizes the value in early detection, keen diagnostic evaluation, and cross-collaboration between multiple ophthalmology specialists to optimize healthcare outcomes for patients with uveal effusion syndrome., (© 2024. The Author(s).)

Background: Although brimonidine is currently used in the clinical treatment of glaucoma and rosacea, research of the deep sedative effect on animals after systemic administration is reported firstly and has shown promising results., Methods: The median effective dose (ED 50 ), the median lethal dose (LD 50 ), and the therapeutic index of brimonidine for deep sedation and formalin stimulation assay were determined by various animal experiments. The effect of synergistic anesthesia in rabbits with brimonidine and chloral hydrate was preliminarily evaluated., Results: The ED 50 of brimonidine for highly effective sedation by intraperitoneal injection in rats was calculated to be 2.05 mg kg -1 with a 95% confidence interval (CI) of 1.87 to 2.25 mg kg -1 . The ED 50 of brimonidine for deep sedation by intravenous and intrarectal injection in rabbits was calculated to be 0.087 mg kg -1 with a 95% CI of 0.084 to 0.091 mg kg -1 and 1.65 mg kg -1 with a 95% CI of 1.43 to 1.91 mg kg -1 , respectively. The LD 50 of intraperitoneal brimonidine injection in rats was calculated to be 468 mg kg -1 with a 95% CI of 441 to 497 mg kg -1 and a therapeutic index of 228. Brimonidine has a certain analgesic and heart rate lowering effects., Conclusion: The results confirmed that brimonidine has deep sedation and analgesic effects after systemic administration and has high safety. It can be used in combination with other types of sedative drugs to achieve better effects., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Rosacea is a chronic inflammatory disease with a multifactorial pathogenesis. The wide spectrum of clinical phenotypes, including erythema, telangiectasia, inflammatory papules and pustules, and phyma, demand an individualized approach to treatment. This narrative review offers an updated reference for rosacea management by covering the latest developments in both topical and systemic treatments, including data from newly approved therapies, updates to current treatment modalities and ongoing clinical trials. Although use of benzoyl peroxide as a treatment for rosacea has typically been limited due to irritation, the improved tolerability due to microencapsulation of benzoyl peroxide 5% cream provides a new therapeutic option for patients with rosacea. Minocycline foam and topical ivermectin cream add to our armamentarium of treatment options, particularly for inflammatory papules and pustules. Sarecycline has a narrower spectrum of antibacterial activity, which might reduce the development of antibiotic resistance and disruption of the microbiome compared to other oral antibiotics. Brimonidine gel and oxymetazoline cream provide topical options for redness and flushing. There is emerging evidence about the role of hydroxychloroquine and intradermal botulinum toxin A, which may improve rosacea through their effects on mast cells. The clinical trials pipeline includes agents with a variety of mechanisms, including mast cell stabilization, antimicrobial, anti-inflammatory, and vasoconstrictive effects. However, the clinical pipeline for rosacea appears limited, and there remain important unmet needs for patients with more recalcitrant rosacea or phymatous disease. In addition, there is a need for comparative effectiveness studies to identify the highest value treatment approaches for patients with rosacea., (© 2023. The Author(s).)

Introduction: Brimonidine is a commonly used drug for glaucoma treatment, which has been linked to ocular autoimmune disorders like uveitis and conjunctivitis. Corneal pathology under brimonidine is generally less common., Case Description: Here, we report a 78 -year-old male patient suffering from immune corneal stromal inflammation with hypotony and resulting hypotonic maculopathy after 6 weeks after introduction of brimonidine treatment. Systemic work-up for system autoimmune and infectious diseases was negative. We discontinued brimonidine and administered topical prednisolone under which inflammatory corneal signs and intraocular pressure normalized. Chorioretinal folds persisted after 9 months., Conclusion: Our case report suggests monitoring patients under brimonidine for sterile corneal infiltration.

Purpose: Brimonidine is a highly alpha-2 adrenergic agonist, which provides a potential myopia control effect. This study aimed to examine the pharmacokinetics and concentration of brimonidine in the posterior segment tissue of eyes in guinea pigs. Methods: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was successfully used for brimonidine pharmacokinetics and tissue distribution research in guinea pigs following intravitreal administration (20 μg/eye). Results: Brimonidine concentrations in the retina and sclera were maintained at a high level (>60 ng/g) at 96 h postdosing. Brimonidine concentration peaked in the retina (377.86 ng/g) at 2.41 h and sclera (306.18 ng/g) at 6.98 h. The area under curve (AUC 0-∞ ) was 27,179.99 ng h/g in the retina and 39,529.03 ng h/g in the sclera. The elimination half-life (T 1/2e ) was 62.43 h in the retina and 67.94 h in the sclera. Conclusions: The results indicated that brimonidine was rapidly absorbed and diffused to the retina and sclera. Meanwhile, it maintained higher posterior tissue concentrations, which can effectively activate the alpha-2 adrenergic receptor. This may provide pharmacokinetic evidence for the inhibition of myopia progression by brimonidine in animal experiments.

Introduction: This multicenter, randomized, comparative, and investigator-masked crossover clinical trial sought to compare the efficacy and tolerability of fixed combinations of 0.1% brimonidine/0.5% timolol (BTFC) versus 1% dorzolamide/0.5% timolol (DTFC) as adjunctive therapies to prostaglandin analogues., Methods: A total of 110 patients with open-angle glaucoma or ocular hypertension previously treated with prostaglandin analogue monotherapy were randomized to receive either BTFC or DTFC as adjunctive therapy for 8 weeks. These patients were then crossed over to the alternative treatment arm for another 8 weeks. The reduction in intraocular pressure (IOP) (primary outcome), occurrence of adverse events, ocular discomfort after instillation, and patient preference (secondary outcomes) were recorded through patient interviews., Results: BTFC instillation for 8 weeks reduced IOP by 3.55 mmHg, demonstrating non-inferiority to DTFC instillation (3.60 mmHg; P < 0.0001, mixed-effects model). Although adverse events were rare with both combinations, patients reported greater discomfort with DTFC than with BTFC (P < 0.0001). More patients preferred BTFC (P < 0.0001) over DTFC, as BTFC caused minimal or no eye irritation., Conclusion: As BTFC offered better tolerability than DTFC with comparable reduction in IOP, we recommend it as an alternative for patients who experience ocular discomfort with DTFC-prostaglandin analogue combination therapy., Trial Registration Number: jRCTs051190125., (© 2023. The Author(s).)

Purpose: This article aims to describe a preclinical proof of concept for a novel once-a-day (OD) brimonidine ophthalmic nanosuspension. Methods: The preclinical proof of concept was established using New Zealand white rabbits as animal models. Dose-finding, multiple-dose efficacy, ocular pharmacokinetic, and hemodynamic studies were performed in normotensive rabbits. Steroid-induced ocular hypertension model in rabbits was used to study efficacy in glaucomatous pathophysiology. The test (0.35% OD suspension) and reference (0.15% three times a day [TID] solution) were compared. Results: The intraocular pressure (IOP) reduction was sustained for 0.35% and 0.5% strengths but not for other lower strengths tested or reference strengths. A 0.35% OD suspension reduced IOP >2 mmHg after 24 h of dosing, which was not seen with the reference. After multiple dosing, 0.35% OD suspension reduced IOP by 4-6 mmHg after 24 h, which was comparable to the 0.15% TID reference solution. An ocular pharmacokinetic study showed that the brimonidine was rapidly absorbed and distributed throughout the eye after topical administration. Concentration was higher in tissues with high α 2 receptors, such as cornea-conjunctiva, iris/ciliary body, and choroid/retina. The steady-state concentrations in these organs were also significant after 24 h of the last dose. There was an indication of increased plasma levels, so a hemodynamic study was performed to assess any adverse effects. All hemodynamic parameters were normal and no new unusual safety findings were observed. Conclusions: The study demonstrated that the novel brimonidine 0.35% ophthalmic nanosuspension is both safe and effective when administered OD and is comparable to the marketed reference formulation administered TID.

Purpose: To evaluate the safety and efficacy of repeat injections of Brimonidine Drug Delivery System (Brimo DDS) Generation 2 (Gen 2) containing 400-μg brimonidine in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD)., Design: A phase IIb, randomized, multicenter, double-masked, sham-controlled, 30-month study (BEACON)., Participants: Patients diagnosed with GA secondary to AMD and multifocal lesions with total area of > 1.25 mm 2 and ≤ 18 mm 2 in the study eye., Methods: Enrolled patients were randomized to treatment with intravitreal injections of 400-μg Brimo DDS (n = 154) or sham procedure (n = 156) in the study eye every 3 months from day 1 to month 21., Main Outcome Measures: The primary efficacy endpoint was GA lesion area change from baseline in the study eye, assessed with fundus autofluorescence imaging, at month 24., Results: The study was terminated early, at the time of the planned interim analysis, because of a slow GA progression rate (∼ 1.6 mm 2 /year) in the enrolled population. Least squares mean (standard error) GA area change from baseline at month 24 (primary endpoint) was 3.24 (0.13) mm 2 with Brimo DDS (n = 84) versus 3.48 (0.13) mm 2 with sham (n = 91), a reduction of 0.25 mm 2 (7%) with Brimo DDS compared with sham (P = 0.150). At month 30, GA area change from baseline was 4.09 (0.15) mm 2 with Brimo DDS (n = 49) versus 4.52 (0.15) mm 2 with sham (n = 46), a reduction of 0.43 mm 2 (10%) with Brimo DDS compared with sham (P = 0.033). Exploratory analysis showed numerically smaller loss over time in retinal sensitivity assessed with scotopic microperimetry with Brimo DDS than with sham (P = 0.053 at month 24). Treatment-related adverse events were usually related to the injection procedure. No implant accumulation was observed., Conclusions: Multiple intravitreal administrations of Brimo DDS (Gen 2) were well tolerated. The primary efficacy endpoint at 24 months was not met, but there was a numeric trend for reduction in GA progression at 24 months compared with sham treatment. The study was terminated early because of the lower-than-expected GA progression rate in the sham/control group., Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Purpose: To evaluate the concentrations of brimonidine and brinzolamide in the vitreous and aqueous humor after instillation of a 0.1% brimonidine tartrate and 1% brinzolamide fixed-combination ophthalmic suspension., Methods: The present investigation involved patients with macular holes or idiopathic epiretinal membranes who were planning to undergo vitrectomy. One week prior to surgery, the patients received twice-daily topical treatment with 0.1% brimonidine tartrate and 1% brinzolamide fixed-combination ophthalmic suspension. Before vitrectomy, vitreous and aqueous humor samples were collected, and the mean concentrations of brimonidine and brinzolamide were determined through liquid chromatography-tandem spectrometry., Results: Ten eyes (nine phakic and one pseudophakic eyes; 10 patients) were examined. The concentration of brimonidine in vitreous and aqueous humor samples was 5.02 ± 2.24 and 559 ± 670 nM, respectively. The concentration of brimonidine in the vitreous humor, which is needed to activate α2 receptors, was >2 nM in all patients. The concentration of brinzolamide was 8.96 ± 4.65 and 1100 ± 813 nM, respectively. However, there was no significant correlation between the concentrations of brimonidine in the vitreous and aqueous humor samples., Conclusions: Sufficient concentrations of brimonidine were detected in all vitreous samples. The dissociated correlation of the drug concentrations between aqueous and vitreous humors implies the possibility of another pathway to vitreous humor, different from the pathway to aqueous humor.

Glaucoma is the leading cause of irreversible blindness, affecting 111 million people by 2040 worldwide. Intraocular pressure (IOP) is the only controllable risk factor for the disease and current treatment options seek to reduce IOP via daily taking eye drops. However, shortcomings of eye drops, such as poor bioavailability and unsatisfied therapeutic effects, may lead to inadequate patient compliance. In this study, an effective brimonidine (BRI)-loaded silicone rubber (SR) implant coated with polydimethylsiloxane (BRI@SR@PDMS) is designed and fully investigated for IOP reduction treatment. The in vitro BRI release from BRI@SR@PDMS implant reveals a more sustainable trend lasting over 1 month, with a gradually declined immediate drug concentration. The carrier materials show no cytotoxicity on human corneal epithelial cells and mice corneal epithelial cells in vitro . After administrated into rabbit's conjunctival sac, the BRI@SR@PDMS implant releases BRI in a sustained fashion and effectively reduces IOP for 18 days with great biosafety. In contrast, BRI eye drops only maintain IOP-lowering effect for 6 h. Therefore, as a substitute of eye drops, the BRI@SR@PDMS implant can be applied as a promising non-invasive platform to achieve long-term IOP-lowering in patients suffering from ocular hypertension or glaucoma., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)

Glaucoma is a chronic eye disease in which the pressure inside the eye increases and leads to damage to the optic nerve, and eventually causes blindness. In this disease, it is often necessary to use a multi-drug treatment system. There is a fixed combination of timolol maleate and brimonidine tartrate among the combination drugs in glaucoma treatment. Liposomes are one of the most important targeted drug delivery systems to eye tissue, which leads to improved drug permeability and durability in ocular tissue. In this study, thin layer hydration was used to make liposomal formulations containing timolol maleate (TM) and brimonidine tartrate (BT). After the necessary evaluations, one of the eight initial formulations was selected as an optimization formulation. Then, characteristics such as drug loading percentage, particle size, pH, zeta potential, and drug release were performed on the optimized formulation. The study of reducing intraocular pressure was performed on the optimized formulation. This study in total was performed on 18 rabbits in three groups. Hydroxypropyl methylcellulose (HPMC) polymer was injected into the anterior chamber to experimental induce glaucoma. The selected formulation was within the acceptable range of ocular products in terms of physical properties. HPMC polymer injection successfully induced glaucoma in the animal model, resulting in a 79% increase in intraocular pressure. The results showed that the liposomal formulation significantly reduced the intraocular pressure compared to the simple formulation of the aqueous solution, and both formulations were able to significantly reduce the intraocular pressure compared to the control group (P < 0.001). The results also showed that liposomal formulation has a therapeutic effect in reducing intraocular pressure. It seems that the selected liposomal formulation made by thin layer hydration can act as a suitable drug carrier to increase the effectiveness of the fixed combination of timolol maleate and brimonidine tartrate and be proposed as a new drug formulation for targeted and controlled drug delivery in the treatment of glaucoma., (© 2022. Controlled Release Society.)

Competing Interests: None disclosed.

Brimonidine is a highly selective 2-adrenoceptor agonist that lowers intraocular pressure (IOP) by decreasing aqueous humor production and increasing aqueous humor outflow via the uveoscleral route. Brimonidine is used to treat glaucoma and other eye conditions. Brimonidine is a topical medication that is used mainly to treat open-angle glaucoma and ocular hypertension in the eyelids. The purpose of this chapter is to provide a comprehensive discussion of Brimonidine's nomenclature, physiochemical properties, preparation methods, identification procedures, and numerous qualitative and quantitative analytical techniques, as well as its ADME profiles and pharmacological effects. In addition, the chapter contains numerous approaches for separating brimonidine from other medications in combination formulations utilizing chromatographic techniques and other spectroscopic approaches., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Retinal ganglion cell (RGC) axons comprise the optic nerve and carry information to the dorsolateral geniculate nucleus (dLGN), which is then relayed to the cortex for conscious vision. Glaucoma is a blinding neurodegenerative disease that commonly results from intraocular pressure (IOP)-associated injury leading to RGC axonal pathology, disruption of RGC outputs to the brain, and eventual apoptotic loss of RGC somata. The consequences of elevated IOP and glaucomatous pathology on RGC signaling to the dLGN are largely unknown yet are likely to contribute to vision loss. Here, we used anatomic and physiological approaches to study the structure and function of retinogeniculate (RG) synapses in male and female DBA/2J (D2) mice with inherited glaucoma before and after IOP elevation. D2 mice showed progressive loss of anterograde optic tract transport to the dLGN and vGlut2 labeling of RGC axon terminals while patch-clamp measurements of RG synaptic function showed that synaptic transmission was reduced in 9-month and 12-month D2 mice because of the loss of individual RGC axon inputs. TC neuron dendrites had reduced Sholl complexity at 12 months, suggestive of delayed reorganization following reduced synaptic input. There was no detectable change in RGC density in 11- to 12-month D2 retinas, quantified as the number of ganglion cell layer-residing somata immuno-positive for NeuN and immuno-negative for the amacrine marker choline acetyltransferase (ChAT). Thus, observed synaptic defects appear to precede RGC somatic loss. These findings identify glaucoma-associated and IOP-associated deficits in an important subcortical RGC projection target, shedding light on processes linking IOP to vision loss., Competing Interests: The authors declare no competing financial interests., (Copyright © 2022 Smith et al.)

We evaluated switching from brinzolamide 1% or brimonidine 0.1% to a fixed-combination of brinzolamide 1% and brimonidine 0.1%, and then determined the efficacy, safety, and satisfaction associated with these changes in glaucoma patients. This prospective, nonrandomized study evaluated a total of 31 enrolled glaucoma patients who underwent treatment with at least brinzolamide 1% or brimonidine 0.1%. Patients were administered a brinzolamide/brimonidine fixed-combination ophthalmic suspension (BBFC) after being switched from their original brinzolamide 1% or brimonidine 0.1% therapy. All other intraocular pressure (IOP)-lowering medications currently being used were continued. IOP, superficial punctate keratopathy (SPK), and conjunctival hyperemia data obtained at baseline and then at 4 and 12 weeks were evaluated. To assess the changes in treatment satisfaction, this study utilized the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). There was a significant decrease in the mean baseline IOP from 15.7 ± 4.9 mmHg to 13.6 ± 4.4 ( p = 0.001) and 13.5 ± 3.9 mmHg ( p = 0.002) at 4 and 12 weeks, respectively. Evaluation of the incidence of conjunctival hyperemia or SPK score showed there were no significant changes noted at any time point. The TSQM-9 score demonstrated there was a significant increase for effectiveness after switching from brinzolamide 1% or brimonidine 0.1% to BBFC. After switching from brinzolamide 1% or brimonidine 0.1% to BBFC, there was a significant decrease in the IOP. Patients were aware of the effectiveness of switching from brinzolamide 1% or brimonidine 0.1% to BBFC.

Glaucoma is the leading cause of irreversible vision loss worldwide, and reduction of intraocular pressure (IOP) is the only factor that can be interfered to delay disease progression. As the first line and preferred method to treat glaucoma, eye drops have many shortcomings, such as low bioavailability, poor patient compliance, and unsustainable therapeutic effect. In this study, a highly efficient brimonidine (BRI) silicone rubber implant (BRI@SR@TPU implant) has been designed, prepared, characterized, and administrated for sustained relief of IOP to treat glaucoma. The in vitro BRI release from BRI@SR@TPU implants shows a sustainable release profile for up to 35 d, with decreased burst release and increased immediate drug concentration. The carrier materials are not cytotoxic to human corneal epithelial cells and conjunctival epithelial cells, and show good biocompatibility, which can be safely administrated into rabbit's conjunctival sac. The BRI@SR@TPU implant sustainably released BRI and effectively reduced IOP for 18 d (72 times) compared to the commercial BRI eye drops (6 h). The BRI@SR@TPU implant is thus a promising noninvasive platform product for long-term IOP-reducing in patients with glaucoma and ocular hypertension.

Background: Rho kinase inhibitors, such as netarsudil, are a relatively new class of medications recently introduced into the market for the treatment of glaucoma, the leading cause of irreversible blindness in the world. Previous clinical trials have studied netarsudil's efficacy when used as a first- or second-line agent but limited studies have investigated its effectiveness in the real world where it is more commonly used as a third, fourth, or fifth agent in combination with other topical medications. Equally important, prior studies have not compared its effectiveness to its peer medications in these settings., Objective: To compare intraocular pressure (IOP) lowering after initiation of netarsudil or brimonidine therapy in patients with glaucoma using >2 medications for IOP management., Methods: A chart review of 369 eyes from 279 patients followed at a single academic tertiary practice was performed with an institutional review board waiver of consent to compare IOP lowering after prescription of netarsudil (n = 176) versus brimonidine (n = 193) as a third, fourth, or fifth IOP-lowering agent. Patients were identified by querying the electronic medical record for those with a glaucoma-related diagnosis who were prescribed either medication. Five sequential IOP measurements were obtained to determine the mean change in IOP before and after treatment (ΔIOP = mean IOP 4,5 - mean IOP 1,2,3 ). A multilevel linear mixed-effects model assessed the influence of medication (independent variable) on ΔIOP (dependent variable). Additional independent variables of interest included the number of glaucoma medications at baseline, age, sex, glaucoma type and severity, race, and pretreatment IOP. Bootstrap analysis was performed to remove sampling bias and confirm mixed-effects model findings. Kaplan-Meier survival analysis evaluated the probability of requiring additional intervention within 3 years following the date of medication prescription., Results: The unadjusted mean (SD) ΔIOP for netarsudil and brimonidine was -2.20 (4.11) mm Hg and -2.21 (3.25) mm Hg, respectively ( P  = 0.484). The adjusted linear mixed-effects models and bootstrap analysis demonstrated that there was no statistical difference in IOP-lowering effectiveness between the medications. Netarsudil and brimonidine failed to adequately control IOP at similar rates with 42% and 47% probabilities of survival respectively by the 3-year follow-up ( P  = 0.520)., Conclusions: When escalating pharmacologic therapy, the IOP-lowering effect of netarsudil appeared to be similar to that produced by brimonidine. ( Curr Ther Res Clin Exp . 2023; 84:XXX-XXX)., Competing Interests: J. Yohannan is a consultant for Abbvie and Ivastis and receives research support from Genentech. The authors have indicated that they have no other conflicts of interest regarding the content of this article., (© 2022 The Author(s).)

The treatment of persistent erythema and rosacea flushing is extremely challenging, especially for patients with anxiety. The aim of this study was to verify the efficacy of carvedilol in rosacea patients with persistent erythema and flushing. A total of 156 patients were randomized to use oral carvedilol 5 mg bid (twice per day) (n = 105) or topical brimonidine (n = 51) for a 10-week period with 6 weeks of follow-up. Both the efficacy of carvedilol and the status of anxiety/depression were analyzed by patient self-assessment (PSA), clinician erythema assessment (CEA), generalized anxiety disorder (GAD-7), and patient health questionnaire-9 (PHQ-9). Our study found that carvedilol exerted a dramatic reduction in CEA/PSA scores and sting/burning sensation scores in comparison to topical brimonidine. Additionally, carvedilol treatment dramatically improved telangiectasia, erythema, and pigmentation with no obvious side effects. Patients with carvedilol treatment showed an improvement of depression/anxiety, as reflected by lower GAD-7 and PHQ-9 scores than patients with topical brimonidine. Notably, we found carvedilol treatment had better outcomes among patients under 30 years of age with rosacea younger than 30 years old. Conclusively, our findings reveal that carvedilol could quickly and effectively improve facial erythema, which might stem from the improved the status of anxiety/depression., (© 2022 Japanese Dermatological Association.)

Brimonidine is a vasoconstrictive agent used to treat several dermatologic disorders. Here, we review the uses of brimonidine in different aspects of dermatology. We searched keywords including rosacea, erythema, topical brimonidine, dermatology, and skin disease in PubMed, Cochrane, and Google Scholar to collect the related published articles. In a review of 15 articles, we found topical brimonidine improved the facial erythema of rosacea. In addition, it reduced the erythema associated with alcohol flushing syndrome, intense pulsed light therapy, and photodynamic therapy. Furthermore, topical brimonidine was used as a hemostatic agent in dermatosurgery procedures such as Mohs surgery and nail surgery to reduce intra-operative and postoperative bleeding. Some side effects such as erythema, flushing, and burning were reported in a few patients. Based on our findings, brimonidine is a beneficial drug that can be used in various dermatologic disorders with negligible side effects., (© 2022 Wiley Periodicals LLC.)

Purpose: This study aims to compare the cytotoxic, apoptotic, and oxidative effects of preserved and preservative-free forms of brimonidine 0.15% on the human corneal epithelial cell (HCEC) line. Methods: Time-dependent cytotoxicity studies were performed with the Alamar Blue method. For apoptotic studies, PE Annexin V and 7-amino-actinomycin (7-AAD) staining and flow cytometry were performed. Messenger RNA (mRNA) expressions of Bax, Bcl-2 , and caspase-3, -9, -12, and protein expressions of Bax and Bcl-2 were evaluated by quantitative real-time polymerase chain reaction and Western blot method, respectively. Results: Cell viability was 76.4% with the preserved solution and 36.05% with the preservative-free solution at the fifth minute. No significant difference was observed with either solution at the 15-min mark, whereas cell viability did not change significantly after 1 h. In the apoptosis evaluation, it was observed that the preservative-free solution increased the early apoptotic activity to a greater degree ( P  < 0.05). Preservative-free solution also induced gene expression of proapoptotic Bax , caspase-9 and -12, and protein expression of Bax while reducing the protein expression of anti-apoptotic Bcl-2 ( P  < 0.0001). Preserved solution induced only the gene expression of caspase-12, and reduced the protein expression of Bcl-2 ( P  < 0.0001). No significant difference was observed in the reactive oxygen species (ROS) levels of either solution compared with the control group ( P  > 0.05). Conclusion: It was demonstrated that the preserved solution is less cytotoxic to the HCEC line in the early period, has less early apoptotic activity, and does not significantly increase ROS levels.

Introduction: Ocular allergies to brimonidine are frequent in patients treated for glaucoma. There is variability in reporting due to the lack of diagnostic criteria and the absence of cutaneous testing. Many false-negative patch tests (PT) have been described. Alternative methods, such as strip and scratch PT, have been used without a standardized method., Objectives: The primary objective is to identify the best method of cutaneous testing and brimonidine concentration for patch testing. The secondary objective is to identify clinical signs and symptoms suggestive of ocular allergy., Patients and Methods: A retrospective review of patient files suspected of brimonidine ocular allergy was performed. Patch testing method, brimonidine concentration and clinical symptoms were reviewed., Results: Of the 36 patients identified, half tested positive for brimonidine for at least one of the testing methods. The scratch PT demonstrated 17 positive reactions (94% detection rate). Three patients reacted with strip PT. No positive results were found with standard PT. The 5% brimonidine concentration demonstrated the highest sensitivity. The absence of eyelid pruritus was associated with negative testing., Conclusion: In the investigation of ocular allergy to brimonidine, scratch PT proved to be an essential tool. Brimonidine 5% pet. appeared as the most sensitive concentration for scratch PT., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To identify 24-h changes in ocular biometric parameters in subjects with ocular hypertension (OHT), and to determine if an intraocular pressure (IOP)-lowering drug alters these parameters. Methods: Thirty volunteers with OHT (58.6 ± 9.2 years of age) were enrolled in this randomized, double-masked, placebo-controlled, crossover study. Participants self-administered 0.2% brimonidine or placebo 3 times daily for 6 weeks. Measurements of seated and supine IOP, central cornea thickness (CCT), anterior chamber depth (ACD), axial length (AXL), and lens thickness were made at 8 am, 3 pm, 8 pm, and 3 am. Statistical tests were Student's 2-tailed paired t -tests or 2-way analysis of variance (ANOVA) followed by one-way ANOVA and post hoc testing. Results: Time of day had a significant effect on IOP, CCT, ACD, and AXL. In placebo-treated eyes, CCT was greater at 3 am than at any other time ( P  < 0.01), ACD and AXL were greater at 3 am and 8 pm than at 3 pm ( P  < 0.01). Daytime IOPs were higher than nighttime (seated, P  = 0.007; supine, P  = 0.018), and supine IOP at night was higher than seated IOP during the day ( P  < 0.001). Brimonidine did not lower IOP at night nor did it alter the 24-h patterns of CCT, ACD, and AXL. Conclusions: Ocular biometric parameters exhibit characteristic 24-h fluctuations in patients with OHT. At night compared with day, the supine IOP increases, the cornea thickens, the anterior chamber deepens, and the AXL increases. Brimonidine does not alter these parameters at times when it lowers IOP (day) nor when it does not (night). Clinical Trial Registration number: NCT0132419.

We report herein on the effects of all- trans retinoic acid (ATRA) on two-dimensional (2D) and three-dimensional (3D) cultures of human trabecular meshwork (HTM) cells that were treated with transforming growth factor β2 (TGF-β2). In the presence of 5 ng/mL TGF-β2, the effects of ATRA on the following were observed: (1) the barrier function of the 2D HTM monolayers, as determined by trans -endothelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) dextran permeability measurements; (2) a Seahorse cellular bio-metabolism analysis; (3) physical properties, including the size and stiffness, of 3D spheroids; (4) the gene expression of extracellular matrix (ECM) molecules, ECM modulators including tissue inhibitor of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), tight junction (TJ)-related molecules, and endoplasmic reticulum (ER)-stress-related factors. ATRA significantly inhibited the TGF-β2-induced increase in the TEER values and FITC dextran permeability of the 2D monolayers, while an ATRA monotreatment induced similar effects as TGF-β2. A real-time metabolic analysis revealed that ATRA significantly inhibited the TGF-β2-induced shift in metabolic reserve from mitochondrial oxidative phosphorylation to glycolysis in 2D HTM cells, whereas ATRA alone did not induce significant metabolic changes. In contrast, ATRA induced the formation of substantially downsized and softer 3D spheroids in the absence and presence of TGF-β2. The different effects induced by ATRA toward 2D and 3D HTM cells were also supported by the qPCR analysis of several proteins as above. The findings reported here indicate that ATRA may induce synergistic and beneficial effects on TGF-β2-treated 2D- and 3D-cultured HTM cells; those effects varied significantly between the 2D and 3D cultures.

Objectives: To investigate the intraocular pressure (IOP)-lowering efficacy, safety, and treatment tolerability of brinzolamide/brimonidine fixed combination (BBFC) in maximum medical therapy., Materials and Methods: The medical records of 92 patients with glaucoma or ocular hypertension who had previously been treated with a different antiglaucomatous regimen and were switched to a treatment regimen that included BBFC were retrospectively analyzed. Patients were divided into 4 groups including 22, 20, 27, and 23 patients based on previous glaucoma treatment. All patients received maximum medical treatment regimen by adding a combination of beta blocker-prostaglandin analogue therapy along with BBFC. IOP values at baseline and month 1, month 3 and month 6 after starting BBFC and ocular adverse effects at follow-up visits were evaluated., Results: The mean age of all patients was 62.7±16.6 years (range: 18-90). Fifty-two patients (56.5%) were women and 40 (43.5%) were men. Forty-eight (52.2%) patients had primary open-angle glaucoma, 35 (38.0%) had pseudoexfoliation glaucoma, and 9 (9.8%) had ocular hypertension. The IOP of the all eyes was 21.1±4.8 mmHg (range: 17-25) before and 17.6±3.7 mmHg, 17.3±3.4, and 17.0±3.5 mmHg at month 1, 3, and 6 after the introduction of BBFC, respectively (p<0.001 for all time points compared to baseline). In all 4 groups, a significant decrease in IOP was observed at month 1, 3, and 6 follow-ups compared to baseline after the introduction of BBFC. The mean number of antiglaucoma drops was significantly reduced from 2.5±0.6 at baseline to 2 after BBFC (p<0.001). The most frequent ocular adverse event was ocular allergic reactions reported in 8 patients (8.7%), conjunctival hyperemia in 5 patients (5.4%), and ocular discomfort in 2 patients (2.5%)., Conclusion: Maximum medical therapy with BBFC provides significant IOP reduction and antiglaucoma therapy simplification with a favorable safety profile in patients with glaucoma.

Glaucoma is treated by frequent instillation of 0.2% w/v brimonidine tartrate eye drop solution, which showed poor ocular bioavailability of 1-3%. Medicated contact lenses can be used to improve the ocular drug bioavailability. However, drug loading in the contact lens matrix showed high burst release and changes the optophysical properties of the contact lens material. In this paper, a novel brimonidine loaded silica nanoparticles-laden silicone contact lenses (Bri-Si) were designed to achieve controlled drug delivery without altering the optophysical properties of the contact lens. Silica nanoparticles were prepared by polymerizing octadecyltrimethoxysilane (OTMS) molecules at the oil/water interface of microemulsion. Traditional soaking method (Bri-SM), direct brimonidine-loading method (Bri-DL) and microemulsion-laden contact lens (Bri-ME) were developed for comparison. The Bri-Si lens showed improved swelling, transmittance, oxygen permeability and lysozyme adherence compared to Bri-SM, Bri-DL and Bri-ME lenses. The Bri-DL lens showed high brimonidine leaching during extraction and sterilization steps, with low cumulative drug release. While, Bri-Si lens show controlled brimonidine release for 144 h. In a rabbit tear fluid model, the Bri-Si lens showed high brimonidine concentration for 96 h compared to Bri-ME lens and eye drop therapy. Based on histopathological studies of cornea, the Bri-Si lens was found to be safe for human applications. The data demonstrated the novel application of silica nanoparticles to control brimonidine release from the contact lens without altering the optophysical properties of the contact lens.

We report herein on the effects of brimonidine (BRI), an α2-adrenergic agonist, on two-dimensional (2D) and three-dimensional (3D) cell-cultured TGF-β2-untreated and -treated human trabecular meshwork (HTM) cells. In the presence of TGF-β2 (5 ng/mL), (1) the effects of BRI on (1) the 2D HTM monolayers' barrier function were investigated as estimated using trans-endothelial electrical resistance (TEER) measurement and FITC dextran permeability; (2) real-time analyses of cellular metabolism using a Seahorse Bioanalyzer; (3) the largeness and hardness of 3D spheroids; and (4) the expression of genes that encode extracellular matrix (ECM) proteins, including collagens (COL) 1, 4, and 6; fibronectin (FN) and α-smooth muscle actin (α-SMA); ECM modulators, including a tissue inhibitor of matrix proteinase (TIMP) 1-4; matrix metalloproteinase (MMP) 2, 9, and 14; and several endoplasmic reticulum (ER) stress-related genes, including the X-box-binding protein 1 (XBP1), the spliced XBP1 (sXBP1), glucose-regulated protein (GRP)78, GRP94, and CCAAT-enhancer-binding protein homologous protein (CHOP). BRI markedly inhibited the TGF-β2-induced increase in the values of TEER of the 2D cell monolayer and the hardness of the 3D spheroids, although it had no effect on their sizes. BRI also cancelled the TGF-β2-induced reduction in mitochondrial maximal respiration but had no effect on the glycolytic capacity. In addition, the gene expression of these molecules was quite different between the 2D and 3D cultures of HTM cells. The present observations found in this study indicate that BRI may beneficially affect TGF-β2-induced changes in both cultures, 2D and 3D, of HTM cells, although their structural and functional properties that were altered varied significantly between both cultures of HTM cells.

Rosacea is a chronic cutaneous disorder affecting primarily the face, characterized by erythema, transient or persistent, telangiectasia, and inflammatory lesions including papulo-pustules and swelling. The essential component of the disease is the persistent erythema of facial skin. Episodes of flushing (acute-subacute intermittent vasodilation) are common. Swelling and erythema of the nose along with dilatation of the pilosebaceous poral orifices, known as rhinophyma, can be noted in chronic cases. Rosacea affects up to 10% of the world population and is especially noted in fair-skinned individuals aged 35-50. Women are affected more often than men. Several treatment modalities including topical medications, systemic drugs, lasers, and light-based therapies have been used for the management of rosacea with variable results. Topical medications such as azelaic acid, metronidazole, and sulfacetamide/sulfur, oral antibiotics such as tetracyclines, and oral retinoids alone or, most commonly, in combination form the mainstay of treatment. Light therapies such as intense pulsed light and pulsed dye laser are best used for the erythemato-telangiectatic type. Topical brimonidine, oxymetazoline, ivermectin, tacrolimus, pimecrolimus, low-dose modified-release tetracyclines and botulinum toxin are the new additions to the therapeutic armamentarium. This article provides a comprehensive review of the various therapies used for rosacea., (© 2022 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Quantitation of ocular drug metabolism is important, but only sparse data is currently available. Herein, the pharmacokinetics of four drugs, substrates of metabolizing enzymes, was investigated in albino rabbit eyes after intracameral and intravitreal administrations. Acetaminophen, brimonidine, cefuroxime axetil, and sunitinib and their corresponding metabolites were quantitated in the cornea, iris-ciliary body, aqueous humor, lens, vitreous humor, and neural retina with LC-MS/MS analytics. Non-compartmental analysis was employed to estimate the pharmacokinetic parameters of the parent drugs and metabolites. The area under the curve (AUC) values of metabolites were 12-70 times lower than the AUC values of the parent drugs in the tissues with the highest enzymatic activity. The ester prodrug cefuroxime axetil was an exception because it was efficiently and quantitatively converted to cefuroxime in the ocular tissues. In contrast to the liver, sulfotransferases, aldehyde oxidase, and cytochrome P450 3A activities were low in the eye and they had negligible impact on ocular drug clearance. With the exception of esterase substrates, metabolism seems to be a minor player in ocular pharmacokinetics. However, metabolites might contribute to ocular toxicity, and drug metabolism in various eye tissues should be investigated and understood thoroughly., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Oxidative stress is to upregulate the pentose phosphate pathway (PPP). The PPP consists of two functional branches, glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconaste dehydrogenase (6PGD). Glutathione reductase (GR) has a significant role in catalyzing an oxidized glutathione form into a reduced form. The purpose of this study is to investigate the effects of brimonidine and proparacaine on the activity of 6PGD, G6PD, and GR enzymes purified from human erythrocytes. Brimonidine displayed considerable inhibition profile against G6PD with IC 50 value and K I constant of 29.93 ± 3.56 and 48.46 ± 0.66 μM, respectively. On the other hand, proparacaine had no inhibitory effect against G6PD. K I values were found to be 66.06 ± 0.78 and 811.50 ± 11.13 μM for brimonidine and proparacaine, respectively, for 6PGD. K I values were found to be 144.10 ± 2.01 and 1,654.00 ± 26.29 μM for brimonidine and proparacaine, respectively, for GR. Herein, also in silico molecular docking studies were performed between drugs and enzymes., (© 2021 International Union of Biochemistry and Molecular Biology, Inc.)

Low bioavailability of topically applied drugs remains a significant challenge for long-term glaucoma therapy. To enhance drug delivery efficiency, we developed dendrimer gel particles that collectively exhibit structural benefits of dendrimer, hydrogel, and particles, using the inverse emulsion method coupled with the highly efficient aza-Michael addition reaction (IEaMA). This hierarchical approach would maximize the utility of the structural features of existing ocular drug delivery systems. We have tested the delivery efficiency and efficacy of two first-line antiglaucoma drugs, brimonidine tartrate (BT) and timolol maleate (TM), which were loaded into dendrimer gel particles of various sizes, i.e., nDHP (nano-in-nano dendrimer hydrogel particles, ~200 nm), μDHP3 (3 μm), and μDHP10 (9 μm). We found that nDHP was superior to μDHP3 and μDHP10 in terms of cytocompatibility, degradability, drug release kinetics, and corneal permeability. The nDHPs increased drug corneal permeability by 17-fold compared to plain drug solution and enabled zero-order prolonged drug release kinetics. The nDHP-based formulation demonstrated pronounced IOP-lowering effects in both single-dose test and 7-day chronic daily dosing test in both Brown Norway rats and glaucoma mice. Taken together, we have developed nano-in-nano dendrimer gel particles for precise dosing and enabling sustained and synergistic efficacy of antiglaucoma drugs, which could be clinically impactful for improving glaucoma treatment.

Spontaneous expulsive suprachoroidal hemorrhage is a rare ocular condition, which usually occurs after sudden decompression of the eyewall. Most of the cases of expulsive hemorrhage reported had a predisposing glaucoma with the combination of corneal pathology. We are reporting a case of spontaneous expulsive suprachoroidal hemorrhage in a glaucoma patient probably due to perpetuated inflammatory reaction and frequent eye rubbing induced by allergic reaction to topical alpha adrenergic agonist in a compromised cornea.