-
Advances in Therapy Aug 2023Multidrug regimens for glaucoma treatment often result in adherence issues due to inconvenience; these issues may be improved with fixed-dose combination drugs. The... (Randomized Controlled Trial)
Randomized Controlled Trial
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 α-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.
Topics: Male; Adult; Humans; Brimonidine Tartrate; Glaucoma, Open-Angle; Ocular Hypertension; Prospective Studies; Hyperemia; Endothelial Cells; Intraocular Pressure; Ophthalmic Solutions; Antihypertensive Agents; Quinoxalines
PubMed: 37330927
DOI: 10.1007/s12325-023-02534-w -
BMC Ophthalmology Apr 2024Myopia 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...
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.
Topics: Male; Animals; Guinea Pigs; Brimonidine Tartrate; Myopia; Refractive Errors; Refraction, Ocular; Ophthalmic Solutions; Sensory Deprivation; Disease Models, Animal
PubMed: 38605375
DOI: 10.1186/s12886-024-03433-6 -
Journal of Clinical Medicine Jun 2023To evaluate the concentrations of brimonidine and brinzolamide in the vitreous and aqueous humor after instillation of a 0.1% brimonidine tartrate and 1% brinzolamide...
Ocular Distribution of Brimonidine and Brinzolamide after Topical Instillation of a 0.1% Brimonidine Tartrate and 1% Brinzolamide Fixed-Combination Ophthalmic Suspension: An Interventional Study.
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.
PubMed: 37445209
DOI: 10.3390/jcm12134175 -
Journal of Medical Case Reports Mar 2024This case report is applicable to the field of ophthalmology because there is a paucity of medical literature related to the clinical presentation, diagnosis, and...
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.
Topics: Humans; Male; Aged; Glaucoma, Angle-Closure; Prednisone; Uveal Effusion Syndrome; Intraocular Pressure; Eye; Brimonidine Tartrate
PubMed: 38509616
DOI: 10.1186/s13256-024-04496-1 -
Advances in Therapy Sep 2023This multicenter, randomized, comparative, and investigator-masked crossover clinical trial sought to compare the efficacy and tolerability of fixed combinations of 0.1%... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Humans; Timolol; Glaucoma, Open-Angle; Cross-Over Studies; Antihypertensive Agents; Ophthalmic Solutions; Brimonidine Tartrate; Intraocular Pressure; Prostaglandins, Synthetic; Drug Combinations
PubMed: 37452961
DOI: 10.1007/s12325-023-02589-9 -
Scientific Reports Apr 2024Ripasudil-brimonidine fixed-dose combination (K-232) simultaneously targets three different intraocular pressure (IOP) lowering mechanisms, increasing trabecular...
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 TGFβ2-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.
Topics: Animals; Mice; Brimonidine Tartrate; Aqueous Humor; Intraocular Pressure; Trabecular Meshwork; Isoquinolines; Sulfonamides
PubMed: 38570526
DOI: 10.1038/s41598-024-58212-6 -
International Ophthalmology Apr 2024The ROCK inhibitor ripasudil hydrochloride hydrate was shown to have axonal protective effects in TNF-induced optic nerve degeneration. The α2-adrenoreceptor agonist...
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.
Topics: Humans; Brimonidine Tartrate; Up-Regulation; AMP-Activated Protein Kinases; Optic Atrophy; Axons; Nerve Degeneration; Isoquinolines; Sulfonamides
PubMed: 38598101
DOI: 10.1007/s10792-024-03095-9 -
Ophthalmology and Therapy Dec 2023The factors related to the ocular penetration of drugs after the administration of eye drops in humans have not been examined in detail. Therefore, this study assessed...
INTRODUCTION
The factors related to the ocular penetration of drugs after the administration of eye drops in humans have not been examined in detail. Therefore, this study assessed the influence of patient factors on the intraocular penetration of eye drops.
METHODS
A pooled analysis was performed on the data of 42 participants from three studies to evaluate the ocular pharmacokinetics in humans after the topical application of brimonidine-related eye drops. The patients were scheduled for vitrectomy and received brimonidine-related eye drops (0.1% brimonidine tartrate ophthalmic solution, 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution, or 0.1% brimonidine tartrate and 1% brinzolamide fixed-combination suspension) twice daily for 1 week. We analyzed the effects of patient factors (sex, the presence or absence of lens, age, corneal thickness, corneal endothelial cell density, tear secretion, eye axial length, height, weight and body mass index [BMI]) on brimonidine, timolol and brinzolamide concentrations in the aqueous and vitreous humor after topical application.
RESULTS
The drug concentrations in the aqueous and vitreous humor were not significantly different, regardless of sex or the presence or absence of lens. Age correlated positively with brimonidine (r = 0.3948, p = 0.012) and brinzolamide (r = 0.6809, p = 0.030) concentrations in the aqueous humor; the correlation with timolol showed a trend towards significance (r = 0.6425, p = 0.086). Corneal thickness, corneal endothelial cell density, tear secretion, eye axial length, height and BMI did not correlate with the drug concentrations in the aqueous or vitreous humor. Timolol concentration in the vitreous humor was negatively correlated with weight (r = - 0.8333, p = 0.010).
CONCLUSION
The findings of this study emphasize the necessity of considering individual differences in ocular pharmacokinetics during drug therapy (formulation design of the eye drops and dose regimen).
PubMed: 37676633
DOI: 10.1007/s40123-023-00794-x -
Oman Journal of Ophthalmology 2024A 32-year-old male, with juvenile open-angle glaucoma on chronic antiglaucoma therapy and recently introduced brimonidine eye drops to the treatment regimen, developed...
A 32-year-old male, with juvenile open-angle glaucoma on chronic antiglaucoma therapy and recently introduced brimonidine eye drops to the treatment regimen, developed bilateral follicular conjunctivitis with subepithelial infiltrates (SEIs) initially resembling common infectious keratoconjunctivitis entities. The persistent nature of the conjunctivitis, the lack of positive conjunctival cultures, the absence of systemic symptoms, the full resolution of the condition upon discontinuation of antiglaucoma drops, and the commencement of topical steroids, along with the reappearance of SEIs upon reintroducing brimonidine; suggested an immune-mediated drug reaction secondary to a Benzalkonium chloride (BAK) preserved brimonidine tartrate 0.2% formulation. The interval between the initiation of brimonidine and the onset of the drug reaction was 13 months and shortened to 1 week upon re-exposure to the drug. The condition fully resolved without further sequelae off brimonidine. Brimonidine is notoriously known for causing ocular allergic reactions, the most common being follicular conjunctivitis, but very few reports exist describing its adverse effects on the cornea. This case highlights that brimonidine may directly or indirectly induce an immune reaction affecting the cornea in the form of SEIs. Brimonidine is, thus, capable of mimicking more commonly recognized infectious disease entities causing keratoconjunctivitis. This is the second report of a similar manifestation linked to its use.
PubMed: 38524330
DOI: 10.4103/ojo.ojo_99_23 -
Journal of Pharmacological Sciences Apr 2024To determine whether combination of topical ripasudil and brimonidine has more effective neuroprotection on retinal ganglion cells (RGCs) following injury to axons...
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-1β 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.
Topics: Mice; Animals; Brimonidine Tartrate; Optic Nerve Injuries; Neuroprotection; Drug Combinations; Isoquinolines; Sulfonamides
PubMed: 38485351
DOI: 10.1016/j.jphs.2024.02.011