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.

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.

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.

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.

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.

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.

Topical brimonidine for the management of facial erythema in rosacea: a histological, histometric, and immunohistochemical study.

BACKGROUND: Facial erythema in rosacea is a troublesome embarrassing presentation with limited options of treatment. Daily brimonidine gel was shown to be an effective modality of treatment. Being unavailable in Egypt and the scarcity of objective evaluation of its therapeutic effect motivated the search for other alternatives. OBJECTIVE: To evaluate the use and effectiveness of topical brimonidine eye drops for the management of facial erythema in rosacea with the aid of objective assessment. METHODS: The study was conducted on 10 rosacea patients presented with facial erythema. Brimonidine tartrate eye drops 0.2% were applied twice daily for 3 months on areas of red facial skin. Punch biopsies were obtained before and after 3 months of treatment. Routine hematoxylin and eosin (H&E) staining as well as CD34 immunohistochemical staining were performed for all biopsies. Sections were examined to detect the changes in the count and the surface area of blood vessels. RESULTS: Evaluation of clinical results showed good improvement of facial redness at the end of treatment (55-75%). Only 10% of subjects expressed rebound erythema. H&E and CD34 stained sections showed an increased count of dilated dermal blood vessels, which decreased significantly after treatment in count and surface area (P = 0.005, and P = 0.004, respectively). CONCLUSION: Topical brimonidine eye drops proved to be effective in managing facial erythema in rosacea, providing an available and cheaper alternative to brimonidine gel. The study improved the subjective evaluation in the context of objective assessment of treatment efficacy.

Brimonidine eye drops reveal diminished sympathetic pupillary tone in comatose patients with brain injury.

BACKGROUND: There is an urgent need for easy-to-perform bedside measures to detect residual consciousness in clinically unresponsive patients with acute brain injury. Interestingly, the sympathetic control of pupil size is thought to be lost in states of unconsciousness. We therefore hypothesized that administration of brimonidine (an alpha-2-adrenergic agonist) eye drops into one eye should produce a pharmacologic Horner's syndrome if the clinically unresponsive patient is conscious, but not if the patient is unconscious. Here, in a first step to explore this hypothesis, we investigated the potential of brimonidine eye drops to distinguish preserved sympathetic pupillary function in awake volunteers from impairment of sympathetic tone in patients in a coma. METHODS: We enrolled comatose patients admitted for acute brain injury to one of the intensive care units (ICU) of a tertiary referral center, in whom EEG and/or neuroimaging for all practical purposes had ruled out residual consciousness. Exclusion criteria were deep sedation, medications with known drug interactions with brimonidine, and a history of eye disease. Age- and sex-matched healthy and awake volunteers served as controls. We measured pupils of both eyes, under scotopic conditions, at baseline and five times 5-120 min after administering brimonidine into the right eye, using automated pupillometry. Primary outcomes were miosis and anisocoria at the individual and group levels. RESULTS: We included 15 comatose ICU patients (seven women, mean age 59 ± 13.8 years) and 15 controls (seven women, mean age 55 ± 16.3 years). At 30 min, miosis and anisocoria were seen in all 15 controls (mean difference between the brimonidine-treated pupil and the control pupil: - 1.31 mm, 95% CI [- 1.51; - 1.11], p < 0.001), but in none (p < 0.001) of the 15 ICU patients (mean difference: 0.09 mm, 95% CI [- 0.12;0.30], p > 0.99). This effect was unchanged after 120 min and remained robust in sensitivity analyses correcting for baseline pupil size, age, and room illuminance. CONCLUSION: In this proof-of-principle study, brimonidine eye drops produced anisocoria in awake volunteers but not in comatose patients with brain injury. This suggests that automated pupillometry after administration of brimonidine can distinguish between the extremes of the spectrum of consciousness (i.e., fully conscious vs. deeply comatose). A larger study testing the "intermediate zone" of disorders of consciousness in the ICU seems warranted.

Brimonidine.

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.

A Case of Sterile Corneal Stromal Infiltration with Hypotonic Maculopathy Under Brimonidine Treatment.

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.

Inflammatory Cells and Lipid Deposits Detected by in Vivo Confocal Microscopy in Brimonidine Tartrate Ophthalmic Solution-Related Corneal Disorders: A Case Series.

We reviewed the medical charts of five patients diagnosed with brimonidine tartrate (BT)-related corneal disorders. A fan-shaped corneal opacity was present in four patients and limbal corneal infiltrations were present in one patient. In vivo confocal microscopy revealed dendritic cells and lipid deposits in the fan-shaped opacity as well as neutrophils in limbal infiltrations. BT instillation was discontinued and topical administration of a corticosteroid was initiated for all patients. The limbal infiltrations improved after BT discontinuation. Conversely, the fan-shaped opacity remained in all affected patients. After a fan-shaped opacity has developed in a patient with a BT-related corneal disorder, the lesion is difficult to resolve. However, limbal infiltrations respond well to treatment. Therefore, BT should be discontinued and anti-inflammatory treatment initiated before a fan-shaped opacity forms.

Cationic liposomes as promising vehicles for timolol/brimonidine combination ocular delivery in glaucoma: formulation development and in vitro/in vivo evaluation.

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.

Evaluation of the Use of Brinzolamide-Brimonidine Fixed Combination in Maximum Medical Therapy.

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.

Systemic toxicity from subcutaneous brimonidine injection successfully treated with naloxone.

Brimonidine is a topical ophthalmic alpha-2 adrenergic agonist solution used to treat glaucoma. The toxidrome includes drowsiness, lethargy, hypotension, bradycardia, and respiratory depression when ingested in infants. We report a case of intentional subcutaneous injection of brimonidine in an elderly patient resulting in hypotension and CNS depression that responded to naloxone. A 73-year-old female with a past medical history significant for glaucoma, hypertension, and indwelling pacemaker presented to the emergency department after injecting her brimonidine tartrate ophthalmic solution subcutaneously (SQ). The patient was not taking any antihypertensive medications or opioids. Initial presentation consisted of lethargy, a paced rhythm of 60 bpm, and blood pressure of 91/24 mmHg with a MAP of 46. Due to central nervous system depression, 3 mg of intranasal naloxone was administered. The patient was treated with intravenous fluids and escalating doses of naloxone and required a continuous infusion. Mental status and vital signs subsequently improved. The patient was admitted to the ICU and naloxone was subsequently weaned over 12 h. Systemic central alpha-2 adrenergic agonist toxicity resulted from SQ brimonidine injection. Central alpha-2 adrenergic agonist overdoses present as sympatholytic effects including CNS depression, bradycardia, hypotension, and may mimic the opioid toxidrome. Brimonidine SQ injection has not previously been reported and this case has similar findings to other central alpha-2 adrenergic agonist poisonings. Naloxone has previously shown variable reversal of CNS depression in central alpha-2 overdose. In this case, high-dose naloxone was useful for reversing CNS depression and hemodynamic instability.

Changes in Ocular Biometric Parameters Over a 24-Hour Period in Ocular Hypertensive Patients.

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.

Intraocular Peak Pressure in Patients Under Treatment With Fixed Combination of Bimatoprost/Timolol/Brimonidine Once Daily Versus Twice Daily.

PRCIS: We investigate the efficacy of triple-fixed-combination of bimatoprost/brimonidine/timolol once and twice a day, demonstrating higher intraocular pressure reduction with once-a-day use, and discuss possible implications based on previous literature. PURPOSE: The purpose of this study was to compare the efficacy of a fixed combination bimatoprost-timolol-brimonidine (Triplenex) instilled once-daily with twice-daily in primary open angle glaucoma. PATIENTS AND METHODS: A randomized clinical trial at a public eye care institution. Thirty patients with primary open angle glaucoma were followed up for 3 months. The right and left eyes of these patients were randomly assigned to once-daily (10:00 pm ) or twice-daily (10:00 am ; 10:00 pm ) regimens of fixed combination bimatoprost-timolol-brimonidine. Intraocular pressure peaks were obtained with the water drinking test before the introduction of this medication (basal WDT0), 1 month (WDT1), 2 months (WDT2), and 3 months (WDT3) after starting the use of the fixed combination of bimatoprost/timolol/brimonidine (Triplenex). Variation from peak intraocular pressure at WDT3 to peak at WDT0 was compared within groups of 2 versus once-daily regimen. RESULTS: Sixty eyes of 30 patients (age: 70.67±9.70 y) were included in this study. Baseline clinical characteristics were comparable between groups. The mean reduction in peak intraocular pressure from WDT0 to WDT3 was 6.1±6.1 mm Hg (30.5%) in the eyes receiving 1 drop per day and 4.3±5.7 mm Hg (21.5%) in the eyes receiving 2 drops per day ( P =0.023). Mean reduction in peak intraocular pressure considering all WDT was also higher in the group with once-a-day treatment (5.90±6.03 vs. 4.46±4.28 mm Hg, P =0.006). CONCLUSION: Fixed combination of bimatoprost 0.01%, brimonidine tartrate 0.15%, and timolol maleate 0.5% once-a-day is more effective in reducing peak intraocular pressure as measured by the WDT than twice-a-day dosing.

Local vasoregulative interventions impact drug concentrations in the skin after topical laser-assisted delivery.

INTRODUCTION: The ability of ablative fractional lasers (AFL) to enhance topical drug uptake is well established. After AFL delivery, however, drug clearance by local vasculature is poorly understood. Modifications in vascular clearance may enhance AFL-assisted drug concentrations and prolong drug dwell time in the skin. Aiming to assess the role and modifiability of vascular clearance after AFL-assisted delivery, this study examined the impact of vasoregulative interventions on AFL-assisted 5-fluorouracil (5-FU) concentrations in in vivo skin. METHODS: 5-FU uptake was assessed in intact and AFL-exposed skin in a live pig model. After fractional CO2 laser exposure (15 mJ/microbeam, 5% density), vasoregulative intervention using topical brimonidine cream, epinephrine solution, or pulsed dye laser (PDL) was performed in designated treatment areas, followed by a single 5% 5-FU cream application. At 0, 1, 4, 48, and 72 h, 5-FU concentrations were measured in 500 and 1500 µm skin layers by mass spectrometry (n = 6). A supplemental assessment of blood flow following AFL ± vasoregulation was performed using optical coherence tomography (OCT) in a human volunteer. RESULTS: Compared to intact skin, AFL facilitated a prompt peak in 5-FU delivery that remained elevated up to 4 hours (1500 µm: 1.5 vs. 31.8 ng/ml [1 hour, p = 0.002]; 5.3 vs. 14.5 ng/ml [4 hours, p = 0.039]). However, AFL's impact was transient, with 5-FU concentrations comparable to intact skin at later time points. Overall, vasoregulative intervention with brimonidine or PDL led to significantly higher peak 5-FU concentrations, prolonging the drug's dwell time in the skin versus AFL delivery alone. As such, brimonidine and PDL led to twofold higher 5-FU concentrations than AFL alone in both skin layers by 1 hour (e.g., 500 µm: 107 ng/ml [brimonidine]; 96.9 ng/ml [PDL], 46.6 ng/ml [AFL alone], p ≤ 0.024), and remained significantly elevated at 4 hours (p ≤ 0.024). A similar pattern was observed for epinephrine, although trends remained nonsignificant (p ≥ 0.09). Prolonged 5-FU delivery was provided by PDL, resulting in sustained drug deposition compared to AFL alone at both 48 and 72 hours in the superficial skin layer (p ≤ 0.024). Supporting drug delivery findings, OCT revealed that increases in local blood flow after AFL were mitigated in test areas also exposed to PDL, brimonidine, or epinephrine, with PDL providing the greatest, sustained reduction in flow over 48 hours. CONCLUSION: Vasoregulative intervention in conjunction with AFL-assisted delivery enhances and prolongs 5-FU deposition in in vivo skin.

In vitro and in vivo evaluation of brimonidine loaded silica nanoparticles-laden silicone contact lenses to manage 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.