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International Journal of Ophthalmology 2020To evaluate the mechanism of which brimonidine tartrate 0.15% causes clinical hypersensitivity.
AIM
To evaluate the mechanism of which brimonidine tartrate 0.15% causes clinical hypersensitivity.
METHODS
A prospective case-control study comparing 8 glaucoma patients with clinical hypersensitivity to brimonidine to a control group consisting 13 healthy volunteers. Blood samples were stimulated with brimonidine 0.15%, timolol 0.5% or brimonidine tartrate/timolol maleate 0.2%/0.5%. Premixed antibodies (CD63/FITC and aIgE/PE) were added for direct staining and whole-blood samples were lysed, fixed and analyzed by a flow cytometer. The basophil population was defined by high IgE cell expression. Degranulation was identified by the expression of the activation molecule CD63.
RESULTS
Basophil activation was not significant when comparing percent of activated basophils of patients and healthy controls after exposure to brimonidine (2.58%, 2.45%, respectively, =0.72). There was a significant suppression of basophil activation when a combination of brimonidine-timolol (0.87%) was compared to timolol (2.27%; =0.012) and to brimonidine alone (2.58%; =0.017).
CONCLUSION
The results of our study do not support the hypothesis that brimonidine induces an immediate allergic reaction. Basophil activation was suppressed by the presence of β-blockers in patients hypersensitive to brimonidine and in healthy individuals. This finding indicates that timolol suppress brimonidine drug reaction by a different mechanism.
PubMed: 32309191
DOI: 10.18240/ijo.2020.03.21 -
Photochemistry and Photobiology Nov 2022We investigated whether topical brimonidine delayed or enhanced the development of squamous cell carcinoma (SCC) when ultraviolet radiation (UVR) was applied to a...
We investigated whether topical brimonidine delayed or enhanced the development of squamous cell carcinoma (SCC) when ultraviolet radiation (UVR) was applied to a well-established murine model. Hairless female mice (n = 125) were randomized into five groups and treated as follows: 1% brimonidine cream before UVR (Group 1), 0.33% brimonidine gel before UVR (Group 2), 1% brimonidine cream after UVR (Group 3), UVR only (control; Group 4) and 1% brimonidine cream only (control; Group 5). For each animal, the first four tumors were recorded and followed until three tumors reached 4 mm or one tumor reached 12 mm in diameter. All animal experiments continued for up to 365 days or until death. Application of 1% brimonidine cream before UVR delayed tumor development relative to control mice treated with UVR alone (P = 0.000006). However, when 0.33% brimonidine gel was applied before UVR (P = 0.313) or 1% brimonidine cream was applied after UVR (P = 0.252), there was no significant delay in tumor development relative to control mice treated with UVR alone. The development of the second and third tumors followed a similar pattern. Topical 1% brimonidine cream applied before UVR exposure delayed SCC development in hairless mice. In contrast, when brimonidine was applied after UVR there was no significant delay in tumor development. These results suggest that the 1% brimonidine cream probably absorbed the UVR, and therefore, a delay in tumor formation was only seen when brimonidine was applied before irradiation. However, there can be multiple reasons for this delay in photocarcinogenesis.
Topics: Female; Mice; Animals; Mice, Hairless; Ultraviolet Rays; Brimonidine Tartrate; Skin Neoplasms; Carcinoma, Squamous Cell; Neoplasms, Radiation-Induced
PubMed: 35338500
DOI: 10.1111/php.13622 -
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 -
Ophthalmology and Therapy Mar 2020This study was aimed to compare ocular tissue distribution and systemic exposure of brimonidine and timolol after single topical administration to rabbits of...
INTRODUCTION
This study was aimed to compare ocular tissue distribution and systemic exposure of brimonidine and timolol after single topical administration to rabbits of fixed-combination ophthalmic solution of 0.1% brimonidine tartrate and 0.5% timolol and single drugs (0.1% brimonidine tartrate ophthalmic solution or 0.5% timolol ophthalmic solution) or concomitant administration of single drugs.
METHODS
Rabbits were treated with a single topical administration of each ophthalmic solution or concomitant administration of single drugs. For concomitant administration, 0.1% brimonidine tartrate was administered after 0.5% timolol instillation successively within 10 s (without interval) or with 5-min intervals. Brimonidine and timolol concentrations in the aqueous humor, retina/choroid, vitreous body, and plasma were determined with liquid chromatography-tandem mass spectrometry.
RESULTS
The area under the curve values of both drugs in the aqueous humor after fixed-combination administration were comparable to those after concomitant administration. The value of brimonidine was comparable to that after 0.1% brimonidine tartrate administration, whereas the value of timolol was 1.6-fold higher than that after 0.5% timolol administration. The plasma area under the curve value of brimonidine did not differ between fixed-combination and single-drug administrations, but that of timolol was higher after fixed-combination administration than after single-drug administration. Similar concentration-time curves of brimonidine were observed in the posterior ocular tissues in all groups. For concomitant administration, both drug concentrations in the aqueous humor without an administration interval were lower than those with 5-min intervals.
CONCLUSION
There was no difference in the effect of formulation compositions on ocular and systemic pharmacokinetics among the ophthalmic solutions, but brimonidine may alter the ocular and systemic absorption of timolol, which is possibly due to its pharmacologic action. We demonstrated the importance of an administration interval in the concomitant administration of these drugs. This concern could be avoided by using a fixed combination of brimonidine and timolol.
PubMed: 31953739
DOI: 10.1007/s40123-020-00229-x -
PloS One 2022To evaluate the concentrations of brimonidine and timolol in the vitreous and aqueous humors after instillation of a 0.1% brimonidine tartrate and 0.5% timolol... (Clinical Trial)
Clinical Trial
Brimonidine and timolol concentrations in the human vitreous and aqueous humors after topical instillation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution: An interventional study.
PURPOSE
To evaluate the concentrations of brimonidine and timolol in the vitreous and aqueous humors after instillation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution.
METHODS
This single-arm open-label interventional study included patients with macular holes or idiopathic epiretinal membranes who were scheduled for vitrectomy. Written informed consent was obtained from all participants. A 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution was administered topically twice daily for 1 week preoperatively. The vitreous and aqueous humors were sampled before vitrectomy, and brimonidine and timolol concentrations were quantified using liquid chromatography-tandem spectrometry. This study was registered with the Japan Registry of Clinical Trials (jRCT, ID jRCTs051200008; date of access and registration: April 28, 2020). The study protocol was approved by the University of Fukui Certified Review Board (CRB) and complied with the tenets of the Declaration of Helsinki.
RESULTS
Eight eyes of eight patients (7 phakic eyes and 1 pseudophakic eye) were included in this study. The mean brimonidine concentrations in the vitreous and aqueous humors were 5.04 ± 4.08 nM and 324 ± 172 nM, respectively. Five of the eight patients had brimonidine concentrations >2 nM in the vitreous humor, which is necessary to activate α2 receptors. The mean timolol concentrations in the vitreous and aqueous humors were 65.6 ± 56.0 nM and 3,160 ± 1,570 nM, respectively. Brimonidine concentrations showed significant positive correlations with timolol concentrations in the vitreous humor (P < 0.0001, R2 = 0.97) and aqueous humor (P < 0.0001, R2 = 0.96).
CONCLUSIONS
The majority of patients who received a 0.1% brimonidine tartrate and 0.5% timolol topical fixed-combination ophthalmic solution showed a brimonidine concentration >2 nM in the vitreous humor. Brimonidine and timolol may be distributed in the ocular tissues through an identical pathway after topical instillation.
Topics: Humans; Aqueous Humor; Brimonidine Tartrate; Ophthalmic Solutions; Timolol; Vitreous Body
PubMed: 36454807
DOI: 10.1371/journal.pone.0277313 -
Nature Communications May 2023Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For...
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.
Topics: Animals; Rabbits; Melanins; Drug Delivery Systems; Brimonidine Tartrate; Peptides; Machine Learning
PubMed: 37130851
DOI: 10.1038/s41467-023-38056-w -
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 -
Graefe's Archive For Clinical and... Nov 2021To evaluate the effect of brimonidine tartrate 0.025% ophthalmic solution on pupil size under scotopic conditions in healthy adults METHODS: Pupil size was measured in...
PURPOSE
To evaluate the effect of brimonidine tartrate 0.025% ophthalmic solution on pupil size under scotopic conditions in healthy adults METHODS: Pupil size was measured in 56 eyes of 28 volunteer participants using a pupillometer under scotopic conditions. Age, gender, and iris color were recorded. Subjects using any ophthalmic medications other than artificial tears were excluded. The pupil size was subsequently measured again under scotopic conditions 60 min after instillation of brimonidine tartrate 0.025% ophthalmic solution.
RESULTS
Statistically significant miosis was seen after instillation of brimonidine tartrate 0.025% (p = 0.04). Average pupil size prior to brimonidine 0.025% instillation was 7.28 ± 1.05 mm, and average pupil size after instillation of brimonidine 0.025% was 6.36 ± 1.68 mm, a reduction of - 23.7% in pupil area. Subjects with light irides demonstrated a greater miotic effect than subjects with dark irides (1.55 mm vs. 0.67 mm, p < 0.0001), with a pupil area reduction of - 37.6% and - 17.4%, respectively. The amount of miosis was independent of initial pupil size.
CONCLUSIONS
Brimonidine tartrate 0.025% causes significant miosis in scotopic settings, although the effect is not as great in darker colored eyes. Further studies are needed to determine the latency and duration of the effect and whether the amount of miosis is clinically significant.
Topics: Adult; Brimonidine Tartrate; Humans; Lubricant Eye Drops; Miotics; Ophthalmic Solutions; Pupil; Quinoxalines
PubMed: 34251483
DOI: 10.1007/s00417-021-05297-8 -
Pharmaceuticals (Basel, Switzerland) Jun 2020Effective pharmacotherapy during glaucoma treatment depends on interventions that reduce intraocular pressure (IOP) and retain the IOP lowering effect for sufficient...
Effective pharmacotherapy during glaucoma treatment depends on interventions that reduce intraocular pressure (IOP) and retain the IOP lowering effect for sufficient time so as to reduce dosing frequency and enhance patient adherence. Combination anti-glaucoma therapy and dosage forms that increase precorneal residence time could therefore constitute a promising therapeutic intervention. The in-situ gel forming self-assembling peptide ac-(RADA)-CONH was evaluated as carrier for the ocular co-delivery of timolol maleate (TM) and brimonidine tartrate (BR). The hydrogel's microstructure and mechanical properties were assessed with atomic force microscopy and rheology, respectively. Drug diffusion from the hydrogel was evaluated in vitro in simulated tear fluid and ex vivo across porcine corneas and its effect on the treated corneas was assessed through physicochemical characterization and histological analysis. Results indicated that TM and BR co-delivery affected hydrogel's microstructure resulting in shorter nanofibers and a less rigid hydrogel matrix. Rapid and complete release of both drugs was achieved within 8 h, while a 2.8-fold and 5.4-fold higher corneal permeability was achieved for TM and BR, respectively. No significant alterations were induced in the structural integrity of the corneas treated with the hydrogel formulation, suggesting that self-assembling peptide hydrogels might serve as promising systems for combination anti-glaucoma therapy.
PubMed: 32575910
DOI: 10.3390/ph13060126