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brimonidine + ripasudil (gra alfa / Graalfa / K232)

✓ Approved

Kowa · ADRA2A · 小分子

什么是 brimonidine + ripasudil？

brimonidine + ripasudil 是一种小分子，由Kowa研发。该药已获批，用于治疗相关适应症，给药途径：Others、Topical。

药物档案

商品名gra alfa, Graalfa, K232
公司Kowa
药物类别小分子
分子靶点ADRA2A, ROCK1
给药途径Others, Topical
状态Approved
来源： ClinicalTrials.gov, Kowa

作用机制

分子靶点

brimonidine + ripasudil 作用于 2 个分子靶点：

ADRA2Aadrenoceptor alpha 2A (ADRAR, ADRA2R)
ROCK1Rho associated coiled-coil containing protein kinase 1 (ROCK-I, P160ROCK)
需要更深入的分析？Noah AI 可解释复杂机制并与同类药物比较。

治疗适应症

brimonidine + ripasudil 针对 1 个适应症，涉及 1 个治疗领域。

治疗领域疾病/病症分期
Eye disordersGlaucoma✓ Approved

相关研究文献

PubMedMolecules (Basel, Switzerland)2026-08-27

Latanoprost Acid-Brimonidine, a New Amide Prodrug for Glaucoma Management Based on the Concept of Sustained Release.

Lin Hong-Jia HJ, Su Shih-Horng SH, Wu Wen-Chung WC

Glaucoma is an ocular disease caused by the improper management of elevated intraocular pressure (IOP). IOP-lowering via topical administration is the first choice to prevent further progression. However, patients may forget to administer their medication, compromising IOP control. To address this problem, a prolonged active pharmaceutical ingredient (API) release system is proposed. A new prodrug (latanoprost acid-brimonidine conjugate, LBJ) was designed and expected to achieve potential long-lasting release of APIs. LBJ was synthesized by two methods. First, Steglich esterification without protecting the hydroxyl group led to a yield of 34.24%. However, the integral ratio between LPA and BM obtained from NMR was 1.25:1, indicating a potential side product resulting from further coupling through the unprotected hydroxyl group in LBJ. As an alternative route, Steglich esterification with a protecting agent, tert-butyldimethylchlorosilane (TBDMSCl), resulted in a yield of 39.35%, and the integral ratio between LPA and BM obtained from NMR was 1:1. The hydrolysis time of LBJ was investigated and compared with that of latanoprost (LP). In the presence of esterase (0.4 U/mL), the hydrolysis times of LP and LBJ were 4 h and 28 days, respectively. The prolonged hydrolysis time results in sustained APIs release, which is beneficial for the development of a sustained drug release system.

PMID 42653864
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PubMedInvestigative ophthalmology & visual science2026-08-13

Targeting RhoA/ROCK Signaling to Modulate Extracellular Matrix Remodeling in Corneal Endothelial Dystrophies.

Schlötzer-Schrehardt Ursula U, Zenkel Matthias M, Pulasani Sai S, Strunz Maria M et al.

Fuchs endothelial corneal dystrophy (FECD) involves pathological extracellular matrix (ECM) accumulation within Descemet's membrane, leading to guttae formation, endothelial dysfunction, and vision impairment. As current treatment is primarily surgical, we investigated whether Rho-associated protein kinase (ROCK) inhibition can reduce fibrotic ECM remodeling in FECD and related corneal endothelial diseases. Endothelial cell-Descemet membrane specimens from FECD, pseudophakous bullous keratopathy (PBK), pseudoexfoliation keratopathy (PEX-K), and normal donor corneas were treated ex vivo with ripasudil or comparator ROCK inhibitors (netarsudil, Y-27632). Complementary in vitro studies used human corneal endothelial cells. ROCK activity, ECM expression, matrix metalloproteinase (MMP) activity, and TGF-β/Smad signaling were analyzed using molecular and imaging techniques. Relative to controls, FECD samples showed constitutive ROCK and TGF-β signaling activation. Ripasudil suppressed ROCK activity and downregulated fibrosis-associated ECM components (including collagens I/III, fibronectin, agrin, TGFBI, clusterin, and tenascin-C), while shifting the MMP-tissue inhibitor of metalloproteinases (TIMP) balance to enhance ECM turnover. These effects were accompanied by reduced ECM deposition and attenuation of TGF-β/Smad signaling, alongside broad transcriptional reprogramming related to fibrosis, inflammation, and cytoskeletal dynamics. Similar ECM-modulating effects were observed in PBK and PEX-K, with ripasudil showing the most pronounced effects among tested inhibitors. ROCK activation contributes to pathological ECM alterations in FECD, and its pharmacologic inhibition with ripasudil suppresses pro-fibrotic ECM production, promotes ECM-remodeling pathways, and supports restoration of ECM homeostasis. These findings suggest ROCK inhibition as a promising non-surgical therapeutic strategy for FECD and related corneal endothelial disorders, warranting further validation in preclinical studies.

PMID 42593179
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PubMedSeminars in ophthalmology2026-08-10

Efficacy and Safety of Aceclidine in Presbyopia, a Systematic Review and Meta -Analysis.

Ibrahim Taha T, Burhan Muhammad M, Bin Shafiq Shaheer S, Razzak Muhammad Junaid MJ et al.

Presbyopia is a prevalent age-related visual disorder affecting approximately 1.8 billion individuals worldwide, with many lacking access to effective correction. Topical pharmacologic therapies such as aceclidine have emerged as potential noninvasive treatments, though their efficacy and safety remain incompletely established. A systematic review and meta-analysis of randomized controlled trials was conducted in accordance with PRISMA guidelines (PROSPERO: CRD420261353653). Databases were searched till March 2026. Adults with presbyopia treated with topical aceclidine, alone or in combination, were included. The primary outcome was ≥ 3-line improvement in distance-corrected near visual acuity (DCNVA). Random-effects models were used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Five trials involving 883 randomized participants were included. In the primary analysis of parallel-group trials, aceclidine significantly increased the likelihood of achieving a ≥ 3-line improvement in distance-corrected near visual acuity compared with placebo (RR 6.28, 95% CI 4.22-9.35; I2 = 2.4%) and compared with aceclidine plus brimonidine (RR 5.05, 95% CI 3.04-8.38; I2 = 28.2%). Secondary analyses of crossover trials demonstrated similar superiority over placebo (RR 14.92, 95% CI 6.77-32.86; I2 = 0%), whereas no significant difference was observed versus combination therapy (RR 1.11, 95% CI 0.90-1.38; I2 = 24.6%). Aceclidine was associated with a higher incidence of treatment-emergent adverse events than placebo (RR 2.23, 95% CI 1.61-3.09). No significant differences were observed in serious adverse events. Aceclidine provides significant short-term improvement in near vision with an acceptable safety profile. Monotherapy may offer slight efficacy benefits over combination regimens. However, limited study numbers and short follow-up necessitate further large-scale, long-term trials.

PMID 42574210
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PubMedAdvanced materials (Deerfield Beach, Fla.)2026-08-03

An E-interwoven Therapeutic Contact Lens System for Rapid Drug Delivery and Precision Dose Monitoring.

Yang Huan H, Zhu Hengtian H, Teng Wenyu W, Huang Heyu H et al.

Precise intraocular pressure (IOP) management and rapid intervention preserve glaucoma vision, yet current ocular delivery systems lack in situ dosage verification, causing treatment blind spots. Here, we develop a wireless therapeutic smart contact lens (SCL) containing a rapid voltage-triggered drug delivery system with a real-time dosage monitoring sensor. The e-interwoven design integrates drug delivery and sensing electrodes in an ultra-thin (17.4 µm) tri-interdigital configuration, which enables the electric field to interact with the drug-loaded hydrogel in the same spatial region. A frequency-matching strategy boosts voltage coupling to drive a brimonidine tartrate-loaded hydrogel to achieve high concentrations in the aqueous humor in 20 min, significantly faster than topical eye drops. The built-in drug dose sensor has a high accuracy <2.8 µg, benefiting from the great linear correlation between wireless frequency drift and release dosage. In acute glaucoma rabbit models, this SCL suppresses peak IOP elevation by 85.7% compared to eye drops. This SCL presents a highly integrated therapeutic platform demonstrating potential for rapid and precise glaucoma treatment.

PMID 42544728
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PubMedJapanese journal of ophthalmology2026-07-18

Real-world effectiveness and safety of a fixed-dose combination of 0.4% ripasudil and 0.1% brimonidine in the management of uveitic glaucoma.

Kusuhara Sentaro S, Matsumiya Wataru W, Mori Sotaro S, Sakamoto Mari M et al.

To evaluate the real-world use, treatment outcomes, and tolerability of the fixed-dose combination of ripasudil 0.4% and brimonidine 0.1% (RBFC) eye drops in patients with uveitic glaucoma (UG). Single-center retrospective case series. Medical records of 39 eyes with open-angle UG treated with RBFC were reviewed. The outcome measures included changes in intraocular pressure (IOP) and glaucoma drug score (GDS) at 12 months, the proportion of eyes with an IOP reduction of ≥2 mmHg at 12 months, the relationship between the duration of UG and the change in IOP at 12 months, changes in IOP in eyes switched from ripasudil plus brimonidine, and adverse events. The median IOP significantly decreased from 19 mmHg at baseline to 14 mmHg at 12 months (p < 0.001), while the median GDS showed no significant change, from 3 at baseline to 4 at 12 months (p = 0.562). At 12 months, 64% of eyes achieved an IOP reduction of ≥2 mmHg. A positive correlation was observed between the duration of UG and the change in IOP at 12 months (rho = 0.539, p < 0.01). In the subgroup analysis restricted to eyes switched from ripasudil plus brimonidine eye drops to RBFC, IOP showed a decreasing trend (p = 0.057). No drug-related adverse events were observed, except for transient conjunctival hyperemia. This real-world study in patients with UG showed that RBFC achieves effective IOP control while reducing treatment burden, with good tolerability, supporting its continued use in UG management.

PMID 42469566
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PubMedArquivos brasileiros de oftalmologia2026-07-15

Diluted brimonidine for improving early postoperative symptoms and subconjunctival hemorrhage after PRK and LASIK.

Napolitano Natália Fernandes Gonçalves NFG, Freitas Ana Vega Carreiro de AVC, Ribeiro Luís Gustavo de Imparato Rodrigues LGIR, Fairbanks Daniella Villas Boas DVB et al.

To assess whether low-concentration brimonidine (0.025%) improves early postoperative signs and symptoms following femtosecond laser-assisted in situ keratomileusis and photorefractive keratectomy without affecting pupil diameter or flap safety. This prospective, randomized, double-masked, contralateral-eye, single-center study was conducted between January and September 2024. In each patient, one eye received 0.025% brimonidine 15-30 min before surgery (mean: 21.3 ± 2.4 min), whereas the fellow eye received 0.15% sodium hyaluronate (control). Primary outcomes on postoperative Day 1 included subconjunctival hemorrhage laser-assisted in situ keratomileusis and patient-reported symptoms (0-10 scale; composite score). Pupil diameter was measured pre-ablation. Statistical analyses included McNemar and paired t tests, with a significant threshold of α=0.05. A total of 124 patients were included (54 laser-assisted in situ keratomileusis and 70 photorefractive keratectomy). Pupil diameter did not differ significantly between brimonidine-treated and control eyes (laser-assisted in situ keratomileusis: 2.63 ± 0.47 vs. 2.69 ± 0.42 mm, p=0.273; photorefractive keratectomy: 2.56 ± 0.44 vs. 2.61 ± 0.39 mm, p=0.116). In laser-assisted in situ keratomileusis, subconjunctival hemorrhage occurred less frequently in brimonidine-treated eyes both intraoperatively (9.3% vs. 46.3%, p<0.001) and on postoperative Day 1 (9.3% vs. 50.0%, p<0.001). Composite symptom scores were significantly lower in brimonidine-treated eyes in both laser-assisted in situ keratomileusis and photorefractive keratectomy groups (p=0.001 for both). Preoperative administration of low-concentration brimonidine (0.025%) significantly reduced subconjunctival hemorrhage in laser-assisted in situ keratomileusis without comprising flap integrity. It also improved early postoperative symptoms in laser-assisted in situ keratomileusis and photorefractive keratectomy, without affecting pupil diameter. These findings support the use of dilute brimonidine as a safe and effective adjunct to enhance the immediate postoperative experience in refractive surgery.

PMID 42454822
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