Effect of intravenous induction with different doses of Esketamine combined with propofol and sufentanil on intraocular pressure among pediatric strabismus surgery: a randomized clinical trial.

BACKGROUND: It is well-established that maintaining stable intraocular pressure (IOP) within the normal range during ophthalmic surgery is important. Esketamine is a commonly used drug in pediatric general anesthesia due to its good analgesic and sedative effects. However, its application in ophthalmic surgery is limited because it can increase IOP. The effect of esketamine combined with other common anesthetics on IOP has been underinvestigated. This study aimed to investigate the effect of different doses of esketamine combined with propofol and sufentanil on IOP during intravenous induction of general anesthesia for pediatric strabismus surgery. METHODS: A total of 181 children with strabismus undergoing unilateral eye surgery under general anesthesia were recruited. Intravenous induction included the use of sufentanil 0.1 µg/kg, propofol 3 mg/kg, and esketamine. Base on the dosage of esketamine, the patients were randomly allocated into three groups: esketamine low (EL) group with 0.25 mg/kg (n = 62), esketamine high (EH) group with 0.5 mg/kg (n = 60), and normal saline (NS) group (n = 59). Hemodynamic parameters, respiratory parameters, and IOP of the non-surgical eye were recorded and compared among the three groups at different time points: before induction (T0), 1 min after induction but before laryngeal mask insertion (T1), immediately after laryngeal mask insertion (T2), and 2 min after laryngeal mask insertion (T3). RESULTS: There were no significant differences in age, gender, body mass index (BMI), and respiratory parameters among the three groups at T0. The IOP at T1, T2, and T3 was lower than that at T0 in all three groups. The EH group (12.6 ± 1.6 mmHg) had a significantly higher IOP than the EL group (12.0 ± 1.6 mmHg) and the NS group (11.6 ± 1.7 mmHg) at T1. However, no difference was found between the EL and NS groups at any time point. Systolic blood pressure (SBP) and heart rate (HR) at T1, T2, and T3 were lower than at baseline, and SBP and HR were higher at T2 than at T1. Additionally, the EH group had a significantly higher HR at T1 than the other two groups. There was no significant difference in diastolic blood pressure (DBP) among the three groups at any time point. CONCLUSION: Propofol combined with sufentanil significantly decreased IOP during the induction of general anesthesia. Although a dose of 0.5 mg/kg esketamine elevated IOP compared to the low-dose and control groups after induction, the IOP remained lower than baseline. 0.25 mg/kg esketamine combined with propofol and sufentanil had little effect on IOP. Therefore, we advocate that a maximum dose of 0.5 mg/kg esketamine combined with propofol and sufentanil will not elevate IOP compared to baseline in pediatric strabismus surgery. TRIAL REGISTRATION: The registration number is ChiCTR2200066586 at Chictr.org.cn. Registry on 09/12/2022.

Treatment and outcome of IgA nephropathy in children from one single center experience.

BACKGROUND: There is no standard recommendation for IgA nephropathy treatment in children. METHODS: This is a retrospective study. From 2012 to 2020, newly diagnosed primary IgAN followed up for at least 1 year were enrolled. The correlation of MESTC scores and clinical index including proteinuria, gross hematuria and renal dysfunction was analyzed. Treatment and clinical response of 6 month, 1year and 3 year at follow up were also analyzed. Complete renal remission was calculated with Kaplan-Meier analysis. RESULTS: The median follow up was 36 months, from 12 months to 87months in 40 IgAN children. Angiotensin-converting enzyme inhibitor (ACEI) was applied to all patients. 30% received ACEI alone; 15% received glucocorticoids; 37.5% received glucocorticoids plus cyclophosphamide, 17.5% received glucocorticoids plus mycophenolate mofetil. Individuals with diffuse mesangial hypercellularity (M1) were more likely to have nephrotic range proteinuria compared to patients with M0 (80% vs. 20%, P < 0.01). Complete renal remission at 6-month, 1-year and 3-year follow up is 50.25%, 70% and 87.5% respectively. Five-year complete renal remission calculated by Kaplan-Meier analysis is 58.4%. Although without significant difference, there is trend of better survival with complete renal remission in group of nephrotic range proteinuria onset. There is no severe adverse effect. CONCLUSION: This study supports the use of glucocorticoids plus immunosuppressive in addition to ACEI in IgA nephrology pediatric patients with proteinuria. We suggest proactive immunosuppressive treatment in IgA nephropathy in children. This is from a single center in China as may not same results in other population.

Sustained release of brimonidine from BRI@SR@TPU implant for treatment of glaucoma.

Glaucoma is the leading cause of irreversible vision loss worldwide, and reduction of intraocular pressure (IOP) is the only factor that can be interfered to delay disease progression. As the first line and preferred method to treat glaucoma, eye drops have many shortcomings, such as low bioavailability, poor patient compliance, and unsustainable therapeutic effect. In this study, a highly efficient brimonidine (BRI) silicone rubber implant (BRI@SR@TPU implant) has been designed, prepared, characterized, and administrated for sustained relief of IOP to treat glaucoma. The in vitro BRI release from BRI@SR@TPU implants shows a sustainable release profile for up to 35 d, with decreased burst release and increased immediate drug concentration. The carrier materials are not cytotoxic to human corneal epithelial cells and conjunctival epithelial cells, and show good biocompatibility, which can be safely administrated into rabbit's conjunctival sac. The BRI@SR@TPU implant sustainably released BRI and effectively reduced IOP for 18 d (72 times) compared to the commercial BRI eye drops (6 h). The BRI@SR@TPU implant is thus a promising noninvasive platform product for long-term IOP-reducing in patients with glaucoma and ocular hypertension.

Effect of ATP-sensitive Potassium Channel Openers on Intraocular Pressure in Ocular Hypertensive Animal Models.

Purpose: To evaluate the effect of ATP-sensitive potassium channel openers cromakalim prodrug 1 (CKLP1) and diazoxide on IOP in three independent mouse models of ocular hypertension. Methods: Baseline IOP was measured in TGFß2 overexpression, steroid-induced, and iris dispersion (DBA/2J) ocular hypertension mouse models, followed by once daily eyedrop administration with CKLP1 (5 mM) or diazoxide (5 mM). The IOP was measured in conscious animals with a handheld rebound tonometer. Aqueous humor dynamics were assessed by a constant perfusion method. Effect of treatment on ocular tissues was evaluated by transmission electron microscopy. Results: CKLP1 decreased the IOP by 20% in TGFß2 overexpressing mice (n = 6; P < 0.0001), 24% in steroid-induced ocular hypertensive mice (n = 8; P < 0.0001), and 43% in DBA/2J mice (n = 15; P < 0.0001). Diazoxide decreased the IOP by 32% in mice with steroid-induced ocular hypertension (n = 13; P < 0.0001) and by 41% in DBA/2J mice (n = 4; P = 0.005). An analysis of the aqueous humor dynamics revealed that CKLP1 decreased the episcleral venous pressure by 29% in TGFß2 overexpressing mice (n = 13; P < 0.0001) and by 72% in DBA/2J mice (n = 4 control, 3 treated; P = 0.0002). Diazoxide lowered episcleral venous pressure by 35% in steroid-induced ocular hypertensive mice (n = 3; P = 0.03). Tissue histology and cell morphology appeared normal when compared with controls. Accumulation of extracellular matrix was reduced in CKLP1- and diazoxide-treated eyes in the steroid-induced ocular hypertension model. Conclusions: ATP-sensitive potassium channel openers CKLP1 and diazoxide effectively decreased the IOP in ocular hypertensive animal models by decreasing the episcleral venous pressure, supporting a potential therapeutic application of these agents in ocular hypertension and glaucoma.

The Roles Played by FP/EP3 Receptors During Pressure-lowering in Mouse Eyes Mediated by a Dual FP/EP3 Receptor Agonist.

Purpose: We investigated the intraocular pressure (IOP)-lowering effect of topical sepetaprost (SPT), a dual agonist of the FP and EP3 receptors. We explored whether certain receptors mediated the hypotensive effect of SPT and outflow facility changes in C57BL/6 mice (wild-type [WT]) and FP and EP3 receptor-deficient mice (FPKO and EP3KO mice, respectively). Methods: IOP was measured using a microneedle. Outflow facility was measured using a two-level, constant-pressure perfusion method. Results: SPT significantly reduced IOP for 8 hours after administration to WT mice. The 2-hour IOP reductions afforded by latanoprost were 15.3 ± 2.5, 1.8 ± 2.0, and 12.3 ± 2.4% in WT, FPKO, and EP3KO mice, respectively; the SPT figures were 13.6 ± 2.1, 5.9 ± 2.7, and 6.6 ± 2.6%, respectively. Latanoprost-mediated IOP reduction was significantly decreased in FPKO mice, and SPT-mediated IOP reduction was reduced in both FPKO and EP3KO mice. At 6 hours after administration, latanoprost did not significantly reduce the IOP in any tested mouse strain. SPT-mediated IOP reduction was reduced in both FPKO and EP3KO mice. IOP reduction at 6 hours was significantly higher after simultaneous administration of selective FP and EP3 receptor agonists, but IOP did not fall on administration of (only) a selective EP3 receptor agonist. SPT significantly increased outflow facility in WT mice, but less so in FPKO and EP3KO mice. Conclusions: The IOP-lowering effect of SPT lasted longer than that of latanoprost. Our data imply that this may be attributable to augmented outflow facility mediated by the FP and EP3 receptors.

Lowering the Intraocular Pressure in Rats and Rabbits by Cordyceps cicadae Extract and Its Active Compounds.

Cordyceps cicadae (CC), an entomogenous fungus that has been reported to have therapeutic glaucoma, is a major cause of blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) death, mostly due to elevated intraocular pressure (IOP). Here, an ethanolic extract of C. cicadae mycelium (CCME), a traditional medicinal mushroom, was studied for its potential in lowering IOP in rat and rabbit models. Data showed that CCME could significantly (60.5%) reduce the IOP induced by microbead occlusion after 56 days of oral administration. The apoptosis of retinal ganglion cells (RGCs) in rats decreased by 77.2%. CCME was also shown to lower the IOP of normal and dextrose-infusion-induced rabbits within 60 min after oral feeding. There were dose effects, and the effect was repeatable. The active ingredient, N6-(2-hydroxyethyl)-adenosine (HEA), was also shown to alleviate 29.6% IOP at 0.2 mg/kg body weight in this rabbit model. CCME was confirmed with only minor inhibition in the phosphorylated myosin light chain 2 (pMLC2) pathway.

The effects of antithrombotic therapy in ab interno trabeculotomy with a spatula-shaped microhook.

To evaluate the effects of the discontinuation of antithrombotic drugs on intraocular pressure (IOP) reduction and complications from ab interno trabeculotomy for patients with glaucoma. We performed a retrospective chart review on the data of patients treated with antithrombotic agents who have undergone ab interno trabeculotomy through Tanito microhook combined with cataract surgery at the Asahi General Hospital and the Tokyo University Hospital, with 6 months of follow-up. The patients were classified into two groups depending on whether they discontinued (AT-) or continued (AT+) antithrombotic therapy during the perioperative phase. The demographics, pre- and postoperative IOP, medication score, best-corrected visual acuity (BCVA), and postoperative complications were analyzed preoperatively and postoperatively at 1 week and 1-6 months. The series included 44 eyes from 44 Japanese patients. The AT- and AT+ groups included 21 eyes from 21 patients and 23 eyes from 23 patients, respectively. The decrease in IOP from the baseline at 1 week postoperative was significantly different between the two groups (p = 0.009), but there were no significant differences observed in the other visits. Hyphema and IOP spikes exceeding 30 mmHg occurred in 10% and 10% of AT- participants, and in 43% and 26% of AT+ participants, respectively. Hyphema and spikes with hyphema occurred more frequently in the AT+ than in the AT- group (p = 0.02 and p = 0.05). The number of patients who had spikes was not significantly different (p = 0.27). In trabeculotomy using the Tanito microhook®, discontinuing antithrombotic therapy had better IOP-lowering effects and less postoperative complications.

Relationships between Intraocular Pressure, Effective Filtration Area, and Morphological Changes in the Trabecular Meshwork of Steroid-Induced Ocular Hypertensive Mouse Eyes.

We investigated whether an inverse relationship exists between intraocular pressure (IOP) and effective filtration area (EFA) in the trabecular meshwork (TM) in a steroid-induced ocular hypertensive (SIOH) mouse model and the morphological changes associated with the reduction of EFA. C57BL/6 mice (n = 15 per group) received either 0.1% dexamethasone (DEX) or saline eye drops twice daily for five weeks. IOP was measured weekly. Fluorescent tracers were injected into the anterior chamber to label EFA at the endpoint. Injected eyes were fixed and processed for confocal microscopy. EFA in the TM was analyzed. Light and electron microscopy were performed in high- and low-tracer regions of six eyes per group. The mean IOP was ~4 mm Hg higher in DEX-treated than saline-treated control eyes (p < 0.001) at the endpoint. EFA was reduced in DEX-treated eyes compared to controls (p < 0.01) and negatively correlated with IOP (R2 = 0.38, p = 0.002). Reduced thickness of juxtacanalicular tissue (JCT) and increased abnormal extracellular matrix in the JCT were found to be associated with reduced EFA. Our data confirm the inverse relationship between EFA and IOP, suggesting that morphological changes in the JCT contribute to the reduction of EFA, thus elevating IOP in SIOH mouse eyes.

Identification of proteomic changes for dexamethasone-induced ocular hypertension using a tandem mass tag (TMT) approach.

Glaucoma, characterized by ocular hypertension, is the second most common cause of vision loss worldwide. The potential mechanism, however, has yet to be elucidated. This study aimed to assess the proteomic changes in the trabecular meshwork (TM) in an observational animal model of Dexamethasone (DEX)-induced OHT. OHT was induced in Wistar rats by applying DEX topically to both eyes for 28 days. Intraocular pressure (IOP) was evaluated and TM protein expressions and protein identification were performed by a TMT-based method for comparing the changes in proteins between DEX-induced OHT and the control group. The results showed that average IOP was elevated significantly in rats of the DEX-induced OHT group compared to controls. Further, a total of 4,804 proteins in the control and DEX-induced OHT group were determined and 4,064 proteins were quantified via TMT proteomics. In total, 292 significantly abundant proteins (173 downregulated and 119 upregulated) were identified between the two groups. Proteins associated with vision, including Crystallin related proteins, filensin, rhodopsin, recoverin, phosducin were lowered in the DEX-induced OHT group relative to the control group. In summary, DEX induced extensive changes in the protein expression of TM tissue. These proteins were found to be candidate biomarkers for personalized treatment and diagnostic research in the future for improving visual health.

Honeycomb Epithelial Edema Associated With Rho Kinase Inhibition: A Case Series and Review of the Literature.

ABSTRACT: The Rho kinase inhibitor netarsudil is a recently approved therapeutic option for the management of increased intraocular pressure in the United States. Although phase 3 clinical trials noted corneal changes related to the medication-namely, nonvisually-significant corneal verticillata-descriptions of a unique form of cystic epithelial edema began to surface as netarsudil (and its sister drug ripasudil, approved in Japan) gained widespread use. This series adds 3 new cases and reviews the current literature on this unique side effect.

One-Pot Procedure for the Synthesis of Asymmetric Substituted Ureido Benzene Sulfonamides as Effective Inhibitors of Carbonic Anhydrase Enzymes.

We report a one-pot procedure for the synthesis of asymmetrical ureido-containing benzenesulfonamides based on in situ generation of the corresponding isocyanatobenezenesulfonamide species, which were trapped with the appropriate amines. A library of new compounds was generated and evaluated in vitro for their inhibition properties against a representative panel of the human (h) metalloenzymes carbonic anhydrases (EC 4.2.1.1), and the best performing compounds on the isozyme II (i.e., 7c, 9c, 11g, and 12c) were screened for their ability to reduce the intraocular pressure in glaucomatous rabbits. In addition, the binding modes of 7c, 11f, and 11g were assessed by means of X-ray crystallography.

In Situ Gelling Electrospun Ocular Films Sustain the Intraocular Pressure-Lowering Effect of Timolol Maleate: In Vitro, Ex Vivo, and Pharmacodynamic Assessment.

Most common intraocular pressure (IOP) reduction regimens for the management of glaucoma include the topical use of eye drops, a dosage form that is associated with short residence time at the site of action, increased dosing frequency, and reduced patient compliance. In situ gelling nanofiber films comprising poly(vinyl alcohol) and Poloxamer 407 were fabricated via electrospinning for the ocular delivery of timolol maleate (TM), aiming to sustain the IOP-lowering effect of the ß-blocker, compared to conventional eye drops. The electrospinning process was optimized, and the physicochemical properties of the developed formulations were thoroughly investigated. The fiber diameters of the drug-loaded films ranged between 123 and 145 nm and the drug content between 5.85 and 7.83% w/w. Total in vitro drug release from the ocular films was attained within 15 min following first-order kinetics, showing higher apparent permeability (Papp) values across porcine corneas compared to the drug's solution. The fabricated films did not induce any ocular irritation as evidenced by both the hen's egg test on chorioallantoic membrane and the in vivo Draize test. In vivo administration of the ocular films in rabbits induced a faster onset of action and a sustained IOP-lowering effect up to 24 h compared to TM solution, suggesting that the proposed ocular films are promising systems for the sustained topical delivery of TM.

Elevated intraocular pressure in children with acute lymphoblastic leukaemia: A prospective study.

Most childhood acute lymphoblastic leukaemia (ALL) protocols include high-dose steroid therapy. However, the known potential of high-dose steroids to significantly elevate intraocular pressure (IOP) and lead to glaucomatous optic neuropathy has not been intensively investigated in children with ALL. Moreover, as children with ALL do not routinely undergo IOP measurements, the need for IOP monitoring and therapy is unknown. We prospectively measured IOP in 90 children with newly diagnosed ALL attending a tertiary paediatric haematology/oncology centre, at diagnosis and at the middle and end of induction therapy. Ocular hypertension (IOP > 21 mm Hg) at any time point was documented in 64 children (71%), and the prevalence increased during induction. Thirty-six children (40%) had elevated IOP at ALL diagnosis before therapy initiation, and stratification to non-standard ALL was a risk factor. IOP reduction therapy was administered to 13 children (14%); none required surgery. Values normalised in all cases. On multivariate logistic regression analysis, dexamethasone therapy was a significant risk factor for ocular hypertension. High body mass index was an additional risk factor in children with elevated IOP at ALL diagnosis. Routine evaluation of IOP during steroid therapy is very important in children with ALL to ensure early intervention which may prevent permanent ocular damage.

Cannabinol modulates neuroprotection and intraocular pressure: A potential multi-target therapeutic intervention for glaucoma.

OBJECTIVES: Glaucoma is characterized by progressive damage of the retinal ganglion cells (RGCs), resulting in irreversible vision loss. Cannabinoids (CBs) ameliorate several factors that contribute to the progression of glaucoma, including increased intraocular pressure (IOP), degeneration of RGC and optical nerve (ON) damage. However, a direct correlation of specific CBs with the molecular events pertaining to glaucoma pathology is not well established. Therefore, this study aims to evaluate the role of cannabinol (CBN) on RGC protection, modulation of IOP, and its effects on the level of extracellular matrix (ECM) proteins using both in vitro and in vivo models of glaucoma. METHODS AND RESULTS: When exposed to elevated hydrostatic pressure, CBN, in a dose-dependent manner, protected differentiated mouse 661W retinal ganglion precursor-like cells from pressure-induced toxicity. In human trabecular meshwork cells (hTM), CBN attenuated changes in the ECM proteins, including fibronectin and α-smooth muscle actin (α-SMA), as well as mitogen-activated protein kinases (phospho-ERK1/2) in the presence or absence of transforming growth factor-beta 2 (TGF-ß2) induced stress. Ocular pharmacokinetic parameters were evaluated post-intravitreal (IVT) CBN delivery in vivo. Furthermore, we demonstrated that IVT-administered CBN improved pattern electroretinogram (pERG) amplitudes and reduced IOP in a rat episcleral vein laser photocoagulation model of glaucoma. CONCLUSION: CBN promotes neuroprotection, abrogates changes in ECM protein, and normalizes the IOP levels in the eye. Therefore, our observations in the present study indicate a therapeutic potential for CBN in the treatment of glaucoma.

Sovesudil (locally acting rho kinase inhibitor) for the treatment of normal-tension glaucoma: the randomized phase II study.

PURPOSE: To evaluate ocular hypotensive efficacy and the safety of sovesudil (formally known as PHP-201), a novel Rho-associated protein kinase (ROCK) inhibitor, in patients with normal-tension glaucoma (NTG). DESIGN: Multicentre, prospective, double-masked, randomized, placebo-controlled, parallel clinical study. METHODS: Patients with NTG (unmedicated baseline IOP ≤ 21 mmHg) were randomized in 3 groups and treated with sovesudil in concentrations of 0.25% and 0.5%, or with a placebo three times daily (TID) for 4 weeks. The primary end-point was the mean diurnal IOP change from the baseline at week 4. Safety was recorded over a 4-week treatment period and the following 2-week observation period. RESULTS: A total of 119 patients were included in the primary efficacy analysis. The mean diurnal IOP change from the baseline at week 4 was -1.56 mmHg for the high-dose group, -1.10 mmHg for the low-dose group and -0.65 mmHg for the placebo group. The difference between the high-dose and the placebo groups was -0.91 mmHg (95% confidence intervals: -1.73, -0.09). 0.5% sovesudil TID met the criteria for superiority to the placebo. The most frequent ocular adverse event among sovesudil-treated patients was conjunctival hyperaemia (24.4% for the high-dose and 17.5% for the low-dose group) and predominately classified as mild. CONCLUSIONS: Sovesudil 0.25% and 0.5% TID showed statistically significant IOP-lowering effects and 0.5% concentration's IOP-lowering effects met the superiority criteria in comparison with the placebo at week 4. Sovesudil was well tolerated with mild adverse events including relatively low incidence of conjunctival hyperaemia in patients with NTG.

Glaucoma e óleo de silicone / Glaucoma and silicone oils

RESUMO O óleo de silicone é um importante tampão utilizado na retinopexia cirúrgica de casos graves de descolamento de retina. O aumento da pressão intraocular e o desenvolvimento de glaucoma secundário são frequentes complicações da sua utilização. A depender do período de aparecimento, diversos mecanismos justificam a ocorrência de tais complicações. Compreender os fatores de riscos e a patogênese do aumento da pressão intraocular associada a aplicação de óleo de silicone em cirurgia retiniana ajuda a orientar o tratamento adequado para cada paciente. O objetivo deste artigo é revisar a literatura sobre a patogenia, a incidência, os fatores de risco e o tratamento desta condição clínica.

ABSTRACT Silicone oil has been an important intraocular tamponade in retinopexy in cases of complicated retinal detachment surgery. The increase of intraocular pressure and development of secondary glaucoma are a known complication of its use. A variety of mechanisms have been proposed for the pathogenesis, depending on the onset. This article aims to review the literature about pathogenesis, the incidence and risk factors, as well as the treatment of this pathology.

Corticosteroid-induced intraocular pressure elevation in the pediatric patients: A protocol for systematic review.

BACKGROUND: Corticosteroids have been one of the most frequently used therapeutics in ophthalmology over the past decades, known for their potent anti-inflammatory and immunosuppressive actions. Intraocular pressure elevation has proven to be a significant ocular side effect that could accompany steroid use. However, the information on ocular-hypertensive corticosteroid response is scant in children. We aim to systematically describe the corticosteroid-induced intraocular pressure elevation in the pediatric age group. METHODS: PubMed, Embase, Web of Science, Cochrane Library, Latin American and Caribbean Health Sciences Literature, and the Chinese Biomedical Literature database will be searched for potential articles from database inception to April 29, 2021. No language restrictions will be applied. Studies involving patients less than 18 years old receiving corticosteroids will be included. We will screen abstracts for relevance, extract data, and assess the risk of bias in duplicate. We will rate the certainty of evidence using the Grading of Recommendations Assessment Development and Evaluation approach. The primary outcome will be the intraocular pressure in pediatric patients group. We will provide a narrative synthesis of the findings. RESULTS: The systematic review will provide high-quality evidence to assess the relationship between dosage, frequency, route of administration, and duration of corticosteroid on intraocular pressure in children. CONCLUSION: The systematic review will provide evidence to assess the safety of corticosteroid for ocular diseases in pediatric population. PROSPERO REGISTRATION NUMBER: CRD42021252298.

The Application of Nitric Oxide for Ocular Hypertension Treatment.

Despite of various therapeutic methods for treating ocular hypertension and glaucoma, it still remains the leading cause of irreversible blindness. Intraocular pressure (IOP) lowering is the most effective way to slow disease progression and prevent blindness. Among the ocular hypotensive drugs currently in use, only a couple act on the conventional outflow system, which is the main pathway for aqueous humor outflow and the major lesion site resulting in ocular hypertension. Nitric oxide (NO) is a commendable new class of glaucoma drugs that acts on the conventional outflow pathway. An increasing number of nitric oxide donors have been developed for glaucoma and ocular hypertension treatment. Here, we will review how NO lowers IOP and the types of nitric oxide donors that have been developed. And a brief analysis of the advantages and challenges associated with the application will be made. The literature used in this review is based on Pubmed database search using 'nitric oxide' and 'glaucoma' as key words.

Effects of Ultrasound Contrast Agent-Mediated Nerve Growth Factor on Apoptosis of Retinal Ganglion Cells in Mice with Glaucoma.

With an increasing incidence in recent years, glaucoma (GL) has gradually become a global public health problem for humans of all ages. Nerve growth factor (NGF) eye drops, with well-documented stable effect in the treatment of GL, can be potentiated by the administration of NGF drugs via ultrasound contrast agent (UCA). This study analyzed the efficacy of NGF+UCA on GL mice and the influencing mechanism on retinal ganglion cells and further explored the pathological changes of GL mice under different UCA irradiation duration. In this study, we established GL mouse models and treated the mouse with NGF+UCA. The effect of NGF+UCA on intraocular pressure in mice was observed; the flash visual evoked potential of mice was compared; the changes of retinal structure, inflammation index, and oxidative stress index were observed, and autophagic protein levels were tested. Finally, the influence of UCA irradiation duration on GL symptoms was observed. The results showed that the intraocular pressure of mice decreased greatly, while their flash visual evoked potential and nervous layer of retina increased, and their ganglion cells showed stronger proliferation activity and weaker apoptosis and autophagy, indicating that UCA-mediated NGF can strongly improve the pathological condition of GL mice. In addition, PI3K/AKT pathway-associated proteins were inhibited in retina under the intervention of NGF+UCA, which further suggests that the influence of UCA-mediated NGF on GL is achieved by inhibiting autophagy of retinal ganglion cells and enhancing their apoptosis via the PI3K/AKT signaling pathway. Moreover, we found that in the treatment of GL, three weeks of UCA irradiation and six weeks caused no significant difference in the pathological manifestations and ganglion cells of mice, while after six weeks of irradiation, the level of NLRP3 in mice increased. In conclusion, UCA-mediated NGF can significantly improve the pathological condition of GL mice and improve the apoptosis of retinal ganglion cells by inhibiting autophagy, which is associated with the inhibition of the PI3K/AKT signal pathway. In terms of selection of UCA irradiation duration, three weeks of irradiation is enough to yield good clinical results.

Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2).

OBJECTIVE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). RESULTS: Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2-7.4, 6.5-7.8, and 6.1-6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. CONCLUSIONS: The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma. CLINICALTRIALS. GOV IDENTIFIER: NCT02250651.