[Topical application of hypotensive drugs for the prevention of intraocular pressure elevation after intravitreal injections of anti-VEGF drugs]. / Mestnoe primenenie gipotenzivnykh preparatov s tsel'yu profilaktiki povysheniya urovnya vnutriglaznogo davleniya posle intravitreal'nykh in"ektsii anti-VEGF-preparatov.

The management protocol for patients with neovascular age-related macular degeneration (nAMD) involves multiple intravitreal injections (IVI) of anti-VEGF drugs. The ability to reduce the peak intraocular pressure (IOP) rise is greatly important in clinical practice. PURPOSE: This study evaluates the effect of topical hypotensive drugs on the short-term IOP rise after IVI of anti-VEGF drugs in patients with nAMD. MATERIAL AND METHODS: The prospective study included 80 patients with newly diagnosed nAMD. Before the start of treatment, the patients were divided into 4 groups of 20 people each: 1st - controls, who received no prophylactic drugs, in the 2nd, 3rd and 4th groups local instillations of one drop of hypotensive drugs brinzolamide 1%, brinzolamide-timolol, brimonidine-timolol were performed in the conjunctival sac twice: 1 day before the injection (at 20:00) and on the day of the injection 2 hours before the manipulation (at 08:00), respectively. IOP was measured in each patient using ICare Pro non-contact tonometer before injection, as well as 1 min, 30 and 60 min after injection. RESULTS: Prophylactic use of hypotensive drugs was associated with a significant decrease in IOP immediately after IVI compared to the same parameter in the 1st group (p<0.001), the maximum decrease in IOP values was observed when using a fixed combination of brimonidine-timolol by 12.1 mm Hg compared to the controls (p<0.001), the combination of brinzolamide-timolol reduced IOP by 8.5 mm Hg (p<0.001), brinzolamide 1% led to the smallest decrease in IOP - by 5.1 mm Hg (p<0.001). CONCLUSION: Study patients that received instillations of brimonidine-timolol combination of one drop into the conjunctival sac 1 day before the injection and on the day of the injection showed the maximum decrease in IOP compared to patients of the other groups.

Brimonidine as a possible treatment for myopia.

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.

Axonal protection by combination of ripasudil and brimonidine with upregulation of p-AMPK in TNF-induced optic nerve degeneration.

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.

Effect of a fixed combination of ripasudil and brimonidine on aqueous humor dynamics in mice.

Ripasudil-brimonidine fixed-dose combination (K-232) simultaneously targets three different intraocular pressure (IOP) lowering mechanisms, increasing trabecular meshwork outflow and uveoscleral outflow, and reducing aqueous humor production Vascularly, ripasudil induces transient vasodilation, brimonidine transient vasoconstriction. Investigating effects on IOP, aqueous dynamics, and EVP in mice eyes by microneedle and constant-pressure perfusion methods, and on cytoskeletal and fibrotic proteins changes in HTM cells by a gel contraction assay and immunocytochemistry. Ripasudil, K-232, and brimonidine droplets significantly reduced IOP at 30 min, with K-232 sustaining the effect at 60 min. For EVP, only K-232 exhibited reduced EVP until 60 min after instillation. In vitro, ripasudil inhibited gel contractility and TGFß2-induced fibrotic changes, whereas brimonidine did not. K-232 significantly lowered IOPs in mice by combining the effects of ripasudil and brimonidine. Brimonidine alone also showed IOP reductions with enhanced outflow facility, and the drug did not interfere with the effects of ripasudil on the trabecular meshwork outflow; K-232 and ripasudil alone both significantly lowered the EVP and enhanced outflow facility, demonstrating that K-232 efficiently reduces IOPs.

Uveal effusion syndrome: a case report.

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.

Drug combination of topical ripasudil and brimonidine enhances neuroprotection in a mouse model of optic nerve injury.

PURPOSE: To determine whether combination of topical ripasudil and brimonidine has more effective neuroprotection on retinal ganglion cells (RGCs) following injury to axons composing the optic nerve. METHODS: Topical ripasudil, brimonidine, or mixture of both drugs were administered to adult mice after optic nerve injury (ONI). The influence of drug conditions on RGC health were evaluated by the quantifications of surviving RGCs, phosphorylated p38 mitogen-activated protein kinase (phospho-p38), and expressions of trophic factors and proinflammatory mediators in the retina. RESULTS: Topical ripasudil and brimonidine suppressed ONI-induced RGC death respectively, and mixture of both drugs further stimulated RGC survival. Topical ripasudil and brimonidine suppressed ONI-induced phospho-p38 in the whole retina. In addition, topical ripasudil suppressed expression levels of TNFα, IL-1ß and monocyte chemotactic protein-1 (MCP-1), whereas topical brimonidine increased the expression level of basic fibroblast growth factor (bFGF). CONCLUSIONS: Combination of topical ripasudil and brimonidine may enhance RGC protection by modulating multiple signaling pathways in the retina.

Nicotine Diminishes Alpha2-Adrenergic Receptor-Dependent Protection Against Oxidative Stress in H9c2 Cardiomyocytes.

Introduction: Nicotine is a major component of cigarette smoke with various detrimental cardiovascular effects, including increased oxidative stress in the heart. Agonism of α2-adrenergic receptors (ARs), such as with dexmedetomidine, has been documented to exert cardioprotective effects against oxidative stress and related apoptosis and necroptosis. α2-ARs are membrane-residing G protein-coupled receptors (GPCRs) that primarily activate Gi/o proteins. They are also subjected to GPCR-kinase (GRK)-2-dependent desensitization, which entails phosphorylation of the agonist-activated receptor by GRK2 to induce its decoupling from G proteins, thus terminating α2AR-mediated G protein signaling. Objective: In the present study, we sought to examine the effects of nicotine on α2AR signaling and effects in H9c2 cardiomyocytes exposed to H2O2 to induce oxidative cellular damage. Methods and Results: As expected, treatment of H9c2 cardiomyocytes with H2O2 significantly decreased cell viability and increased oxidative stress, as assessed by reactive oxygen species (ROS)-associated fluorescence levels (DCF assay) and superoxide dismutase activity. Both H2O2 effects were partly rescued by α2AR activation with brimonidine in control cardiomyocytes but not in cells pretreated with nicotine for 24 hours, in which brimonidine was unable to reduce H2O2-induced cell death and oxidative stress. This was due to severe α2AR desensitization, manifested as very low Gi protein activation by brimonidine, and accompanied by GRK2 upregulation in nicotine-treated cardiomyocytes. Finally, pharmacological inhibition of adenylyl cyclase (AC) blocked H2O2-dependent oxidative damage in nicotine-pretreated H9c2 cardiomyocytes, indicating that α2AR activation protects against oxidative injury via its classic coupling to Gai-mediated AC inhibition. Discussion/Conclusions: Nicotine can negate the cardioprotective effects of α2AR agonists against oxidative injury, which may have important implications for patients treated with this class of drugs that are chronic tobacco smokers.

Preliminary evaluation of the efficacy and safety of brimonidine for deep sedation.

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 (ED50 ), the median lethal dose (LD50 ), 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 ED50 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 ED50 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 LD50 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.

Improvement of objective ocular redness measured with Keratograph 5M in glaucoma patients after instilling brimonidine drops.

OBJECTIVE: To compare objective ocular redness measured using OCULUS Keratograph 5 M before and after 0.2% brimonidine instillation in glaucoma patients under topical hypotensive treatment. METHODS: 60 eyes from 60 subjects diagnosed with glaucoma or ocular hypertension under hypotensive ocular topical treatment were analyzed. Basal Ophthalmological examination was performed.Outcome variables were OCULUS Keratograph 5 M redness scores (RS) before and after 0.2% brimonidine instillation; overall, bulbar temporal (BT), bulbar nasal (BN), limbar temporal (LT), and limbar nasal (LN); non-invasive average tear film breakup time (Nia-BUT), non-invasive first tear film breakup time (Nif-BUT) and meibography. In addition, the following clinical data were collected: intraocular pressure, type, duration, amount, and preservatives/or not of hypotensive treatment, fluorescein corneal staining score and lower tear meniscus height. RESULTS: All eyes were under topical medication. All redness scores were reduced after brimonidine instillation, mean RS differences were BT 0.82 ± 0.62, BN hyperemia 1.03 ± 0.55, LN hyperemia 0.84 ± 0.49, LT hyperemia 0.71 ± 0.50 and total hyperemia 0.91 ± 0.52 (all p < 0.001). 30 min after brimonidine instillation mean overall RS reduction was 47.97 ± 12.39% (p < 0.001) and after 1 h there was a persistent reduction of overall RS of 45.92 ± 14.27% (p < 0.001). Hyperemia reduction was significant and comparable between preservative and preservative-free group 0.12 ± 0.14 (p > 0.392) and between patient with combination therapy and monotherapy 0.16 ± 0.14 (p > 0.258). CONCLUSION: A significant reduction of conjunctival hyperemia was objectively found in glaucoma patients under topical hypotensive treatment before and after brimonidine instillation. Its fast and long-lasting effect may be useful preoperatively in glaucoma patients to reduce intraoperative bleeding and associated complications.

Development of brimonidine niosomes laden contact lenses for extended release and promising delivery system in glaucoma treatment.

BACKGROUND: Increased intraocular pressure is a common symptom of glaucoma. In severe circumstances, it may result in loss of eyesight. Glaucoma treatment is difficult due to ocular physiological barriers that prevent medications from reaching the afflicted area. Traditional formulations (eye drops) have a short residence period and are rapidly drained away via the nasolacrimal duct, resulting in increased adverse drug responses and lower efficacy. The usage of nanoparticles such as niosomes could be one potential answer to these problems. While niosomes improve drug penetration, they have little effect on ocular retention of the medication. Contact lenses containing niosomes can assist to overcome this disadvantage. OBJECTIVE: This study aims to prepare and evaluate Brimonidine niosomes laden contact lenses for the treatment of Glaucoma. METHODS: Brimonidine niosomes were prepared using thin film hydration method and evaluated. The contact lenses were soaked in the niosomal formulation at varying intervals (3-10 days). Thereafter, the contact lenses were evaluated for %transmittance, %swelling index, drug quantification and in vitro drug release. The pharmacodynamic studies were conducted to assess the reduction in intraocular pressure (IOP) in albino rabbits. The research compared the results of the reduction in intraocular pressure caused by Brimonidine niosomes laden contact lenses with a marketed preparation of niosomes. RESULTS: Higher concentration of the drug was loaded in contact lenses loaded with Brimonidine niosomes compared to the marketed formulation, by soaking method. The contact lenses exhibited an optimal %transmittance of 98.02 ± 0.36 and %swelling index of 50.35 ± 0.57. Increase in the soaking time up to 7 days led to an increase in the drug concentration in the contact lenses. However, no further increase was observed after the 7th day due to saturation of the contact lenses. Brimonidine niosomes laden contact lenses provided a reduction in intraocular pressure that was similar to the marketed preparation. Further, the contact lenses provided extended release up to 20 h. CONCLUSION: Brimonidine niosomes laden contact lenses exhibited superior drug loading through the soaking method, displaying optimal %transmittance and %swelling index. Soaking for 7 days increased drug concentration in contact lenses with no further increase due to saturation. These lenses reduced intraocular pressure like the marketed formulation, offering extended release for 20 h.

The effect of a brinzolamide/brimonidine fixed combination on optic nerve head blood flow in rabbits.

PURPOSE: The purpose of this study was to investigate the effect of a 1% brinzolamide and 0.1% brimonidine fixed combination (BBFC) on ONH blood flow (BF) in rabbits. METHODS: A crossover study was conducted on pigmented rabbits; a physiological saline solution, brinzolamide, or BBFC was administered for eight days. ONH BF, intraocular pressure (IOP) and systemic parameters were measured before the eighth day's first dose and at 6, 9, 12, and 14 hours after the dose. ONH BF was assessed using laser speckle flowgraphy, and mean blur rate (MBR) values were calculated. The percentage against baseline of each parameter was calculated, and intergroup comparisons were performed at each time point. RESULTS: There were no significant differences in the percentage change in systemic parameters. At 6 hours after administration, the BBFC group showed a significantly higher percentage change in large vessel area-MBR (%MV) compared to the control group (98.6±16.8%MV vs. 81.3±7.9%MV, P = 0.03). On the other hand, the brinzolamide group did not show a significant difference. Both the brinzolamide and BBFC groups had significantly lower percentage change in IOP (%IOP) compared to the control group (90.6±5.0%IOP, 93.3±2.9%IOP, and 99.2±1.7%IOP, respectively, P < 0.01). CONCLUSION: BBFC effectively reduces IOP and mitigates diurnal fluctuation-induced decreases in ONH BF.

Novel frontiers in neuroprotective therapies in glaucoma: Molecular and clinical aspects.

In the last years, neuroprotective therapies have attracted the researcher interests as modern and challenging approach for the treatment of neurodegenerative diseases, aimed at protecting the nervous system from injuries. Glaucoma is a neurodegenerative disease characterized by progressive excavation of the optic nerve head, retinal axonal injury and corresponding vision loss that affects millions of people on a global scale. The molecular basis of the pathology is largely uncharacterized yet, and the therapeutic approaches available do not change the natural course of the disease. Therefore, in accordance with the therapeutic regimens proposed for other neurodegenerative diseases, a modern strategy to treat glaucoma includes prescription of drugs with neuroprotective activities. With respect to this, several preclinical and clinical investigations on a plethora of different drugs are currently ongoing. In this review, first, the conceptualization of the rationale for the adoption of neuroprotective strategies for retina is summarized. Second, the molecular aspects highlighting glaucoma as a neurodegenerative disease are reported. In conclusion, the molecular and pharmacological properties of most promising direct neuroprotective drugs used to delay glaucoma progression are examined, including: neurotrophic factors, NMDA receptor antagonists, the α2-adrenergic agonist, brimonidine, calcium channel blockers, antioxidant agents, nicotinamide and statins.

Topical brimonidine induced acute uveal effusion in a patient with nanophthalmos: a case report.

BACKGROUND: We report a case of uveal effusion in a nanophthalmic eye after topical use of brimonidine. CASE PRESENTATION: A 42-year-old male patient with nanophthalmos experienced sudden blurred vision in the right eye after using topical brimonidine when picking up tennis balls repeatedly 6 weeks after bilateral YAG peripheral iridotomy. Ocular examination showed wide choroidal and exudative retinal detachment in the temporal and inferior region, involving the macula. Acute uveal effusion in the right, bilateral nanophthalmos was diagnosed. Oral and topical corticosteroids, combined with topical nonsteroids and atropine led to a complete resolution of the uveal effusion after one month. CONCLUSION: This case suggested a possible causal relationship between the topical use of brimonidine and acute uveal effusion in patients with nanophthalmos. Topical brimonidine should be used with caution in nanophthalmic eyes.

Additive effects of brimonidine tartrate 0.1%/brinzolamide 1% fixed-dose combination in prostaglandin analog-treated Japanese glaucoma patients.

PURPOSE: A brimonidine tartrate 0.1%/brinzolamide 1% fixed-dose combination (BBFC) was recently approved for glaucoma and ocular hypertension treatment in Japan. We investigated the efficacy and safety of BBFC used concomitantly with prostaglandin analogs (PG) or a PG/beta-blocker fixed-dose combination (PG/beta FC). STUDY DESIGN: This was a prospective, open-label, multicenter study. PATIENTS AND METHODS: We enrolled Japanese patients with open-angle glaucoma. BBFC (Ailamide) was concomitantly administered to either the PG or the PG/beta FC group, and intraocular pressure (IOP) and safety were evaluated at 4 and 12 weeks. The groups were stratified into low and high IOP baseline groups based on the median baseline IOP. RESULTS: We enrolled 100 patients, 91 of whom completed the 12-week follow-up. The mean ages were 67.1 and 65.7 years in the PG group (n = 45, baseline IOP of 15.7 ± 2.3 mmHg) and the PG/beta FC group (n = 46, baseline IOP of 16.3 ± 2.3 mmHg), respectively. After BBFC administration, IOPs at 4 and 12 weeks were 13.0 ± 2.0 and 13.0 ± 2.6 mmHg (P < 0.0001) in the PG group, respectively, and 13.7 ± 2.4 and 13.7 ± 2.2 mmHg (P < 0.0001) in the PG/beta FC group, respectively. IOP decreased by - 2.0 ± 1.8 mmHg (P < 0.0001) and -1.9 ± 1.4 mmHg (P < 0.0001) in the low baseline PG group (14.1 mmHg) and low baseline PG/beta FC group (14.8 mmHg) at 12 weeks, respectively. Sixteen adverse events were identified, all of which were common and did not affect visual acuity. CONCLUSIONS: BBFC can be used concomitantly with PG or PG/beta FC to reduce IOP without serious complications.

Assessment of corneal sublayer thickness changes in glaucoma patients using optical coherence tomography and correlation of epithelial layer thinning with dry eye monitoring.

BACKGROUND: In this study, we aimed to assess the central corneal epithelial thickness (CET), central corneal stromal thickness (CST), and total central corneal thickness (CCT) thinning relationships with dry eye development monitoring and underestimated measurement of intraocular pressure (IOP) in primary open-angle glaucoma (POAG) patients treated with timolol, dorzolamide, and brimonidine. METHODS: This longitudinal cohort study included 106 patients with POAG. All patients underwent a detailed ophthalmic examination. In addition, CET, CST, and CCT were measured using anterior segment optical coherence tomography (AS-OCT). Subsequently, the cohort was divided into three groups based on the therapy administered. The Tomec group received monotherapy with benzalkonium chloride (BAK)-preserved timolol + dorzolamide fixed combination. The Alphagan group received monotherapy with purite-preserved brimonidine, and the Combigan group received monotherapy with BAK-preserved timolol + brimonidine fixed combination. RESULTS: CET, CST, and CCT did not show a statistically significant decrease in the Alphagan group (p>0.05). However, the Tomec and Combigan groups showed significantly reduced measurements, except for stromal thickness (p<0.05). Finally, a significant positive correlation was found between changes in tear break-up time (TBUT) and CET during the follow-up period (r = 0.637, p = 0.001). CONCLUSIONS: CET and CCT thinning were higher in the Tomec and Combigan groups than in the Alphagan group. Furthermore, although CCT reduction was significant in the Tomec and Combigan groups, its effect on IOP underestimation was approximately 1%. Furthermore, the positive correlation between CET and TBUT suggests that CET measurement with AS-OCT may also be useful in dry eye monitoring.

Randomized Multicenter Clinical Trial Comparing 0.1% Brimonidine/0.5% Timolol Versus 1% Dorzolamide/0.5% Timolol as Adjuncts to Prostaglandin Analogues: Aibeta Crossover Study.

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.

Patients with glaucoma who require further reduction in intraocular pressure while undergoing monotherapy with prostaglandin analogue ophthalmic solution have been prescribed two enhanced treatment options: 0.1% brimonidine/0.5% timolol fixed combination ophthalmic solution (BTFC) and 1% dorzolamide/0.5% timolol fixed combination ophthalmic solution (DTFC). The Aibeta Crossover Study Group in Japan compared the efficacy and tolerability of fixed combinations of BTFC versus DTFC when an additional fixed combination ophthalmic solution was prescribed in patients with open-angle glaucoma or ocular hypertension who had been treated with prostaglandin analogue monotherapy. We recruited 110 patients previously treated with prostaglandin analogue monotherapy at 20 clinical centers in Japan, then randomly assigned them to two alternative treatment groups: the BTFC to DTFC group or the DTFC to BTFC group, as an adjunctive therapy to prostaglandin analogues for total of 16 weeks. We compared the reduction in intraocular pressure, occurrence of side effects, eye discomfort after instillation, and patient preference between BTFC versus DTFC instillations. The intraocular pressure reduction of BTFC instillation was comparable to that of DTFC instillation, showing non-inferiority to DTFC (3.55 mmHg vs. 3.60 mmHg; P < 0.0001, mixed-effects model). Both eye drops caused few side effects; however, patients felt greater eye discomfort with DTFC than with BTFC (P < 0.0001). Because of less eye irritation, more patients preferred BTFC (P < 0.0001) over DTFC. We can recommend using BTFC for patients who feel eye discomfort with DTFC­prostaglandin analogue combination therapy.

Neurogenic Rosacea Treatment: A Literature Review.

Rosacea is a chronic skin disorder involving central facial erythema secondary to vascular instability and cutaneous inflammation. Rosacea is divided into different subtypes based on the morphology of the rash — erythematotelangiectatic, papulopustular, phymatous, and ocular rosacea. A less-known subtype called neurogenic rosacea has been proposed to categorize patients suffering from rosacea with erythematous flushing and burning sensation that is refractory to traditional treatment. There is minimal data on this subgroup of rosacea patients and its potential treatment options. This review aims to explore current medical literature to define characteristics of neurogenic rosacea and its management. We performed a systematic search of PubMed database and identified 6 articles meeting inclusion criteria with a total of 37 patients with suspected neurogenic rosacea. Combination treatments with topicals (eg, metronidazole, brimonidine), as well as oral medications including vascular (eg, beta blockers), psychiatric (eg, diazepam, duloxetine), neurologic (eg, pregabalin, sumatriptan), and antibiotic agents (eg, rifaximin), were often cited to have better outcomes, but this finding was highly variable between patients. There were isolated reports of effective management with onabotulinumtoxinA intradermal injections and endoscopic thoracic sympathectomy treatment. Current literature supports selecting agents aimed at treating the major symptom pattern (eg, erythema, telangiectasias, burning sensation). Neurogenic rosacea treatment: a literature review. Ivanic MG, Oulee A, Norden A, et al. J Drugs Dermatol. 2023;22(6):566-571. doi:10.36849/JDD.7181  .

Crossover Randomized Study of Pharmacologic Effects of Ripasudil-Brimonidine Fixed-Dose Combination Versus Ripasudil or Brimonidine.

INTRODUCTION: Multidrug regimens for glaucoma treatment often result in adherence issues due to inconvenience; these issues may be improved with fixed-dose combination drugs. The ophthalmic solution of ripasudil-brimonidine fixed-dose combination (RBFC; K-232) is the first treatment combining a Rho kinase inhibitor and an α2-adrenoceptor agonist, and has demonstrated ability to lower intraocular pressure (IOP) and have various effects on conjunctival hyperemia and corneal endothelial cell morphology. This study evaluates the pharmacologic effects of RBFC treatment versus its separate components-ripasudil or brimonidine. METHODS: This single-center, prospective, randomized, open-label, blinded endpoint study with 3 × 3 crossover design randomly assigned healthy adult men to three groups (1:1:1) to undergo consecutive 8-day administration phases (with drug-free intervals of at least 5 days). Subjects received twice-daily instillation of RBFC → ripasudil → brimonidine (group A), ripasudil → brimonidine → RBFC (group B), or brimonidine → RBFC → ripasudil (group C). Endpoints included change in IOP, severity of conjunctival hyperemia, corneal endothelial cell morphology, pupil diameter, and pharmacokinetics. RESULTS: Eighteen subjects were assigned in total (six to each group). RBFC significantly reduced IOP from baseline at 1 h post-instillation on days 1 and 8 (12.7 vs. 9.1 and 9.0 mmHg, respectively; both P < 0.001), and provided significantly greater IOP reductions than ripasudil or brimonidine at several time points. The most common adverse drug reaction with all three treatments was mild conjunctival hyperemia, which transiently increased in severity with RBFC or ripasudil, peaking at 15 min post-instillation. In post hoc analyses, conjunctival hyperemia scores were lower with RBFC than with ripasudil at several time points. Transient morphologic changes in corneal endothelial cells occurred for up to several hours with RBFC or ripasudil, but not with brimonidine. Pupil diameter did not change with RBFC. CONCLUSION: RBFC significantly reduced IOP compared with each agent alone. A combination of each agent's pharmacologic profile was observed in that of RBFC. TRIAL REGISTRATION: Japan Registry of Clinical Trials; Registration No. jRCT2080225220.

Ocular Posterior Segment Distribution and Pharmacokinetics of Brimonidine After Intravitreal Administration in Guinea Pigs.

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 (AUC0-∞) was 27,179.99 ng h/g in the retina and 39,529.03 ng h/g in the sclera. The elimination half-life (T1/2e) 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.

Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery.

Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For many chronic ocular diseases, patient adherence to eye drop dosing regimens and the need for frequent intraocular injections are significant barriers to effective disease management. Here, we utilize peptide engineering to impart melanin binding properties to peptide-drug conjugates to act as a sustained-release depot in the eye. We develop a super learning-based methodology to engineer multifunctional peptides that efficiently enter cells, bind to melanin, and have low cytotoxicity. When the lead multifunctional peptide (HR97) is conjugated to brimonidine, an intraocular pressure lowering drug that is prescribed for three times per day topical dosing, intraocular pressure reduction is observed for up to 18 days after a single intracameral injection in rabbits. Further, the cumulative intraocular pressure lowering effect increases ~17-fold compared to free brimonidine injection. Engineered multifunctional peptide-drug conjugates are a promising approach for providing sustained therapeutic delivery in the eye and beyond.