Topical netarsudil for the treatment of primary corneal endothelial degeneration in dogs.

This study evaluated the tolerability and efficacy of the topical rho-kinase inhibitor netarsudil for canine primary corneal endothelial degeneration (PCED). Twenty-six eyes of 21 client-owned dogs with PCED were enrolled in a prospective, randomized, vehicle control clinical trial and received topical netarsudil 0.02% (Rhopressa®) or vehicle control twice daily (BID) for the first 4 months. Then, all patients received netarsudil for the next 4 or 8 months. Complete ophthalmic examination, ultrasonic pachymetry, Fourier-domain optical coherence tomography, and in vivo confocal microscopy were performed at baseline and 1, 2, 4, 6, 8 and 12 months. Effect of netarsudil on central corneal thickness (CCT), percentage of cornea with edema, and endothelial cell density (ECD) were evaluated by repeated measures ANOVA. Kaplan-Meier curves and log-rank test were used to compare corneal edema and clinical progression of eyes in netarsudil versus vehicle control groups. All dogs developed conjunctival hyperemia in at least one eye while receiving netarsudil. Unilateral transient reticulated intraepithelial bullae and stromal hemorrhage were observed respectively in 2 dogs in the netarsudil group. Two dogs showed persistently decreased tear production while receiving netarsudil, requiring topical immunomodulatory treatment. No significant differences in CCT, ECD, corneal edema or clinical progression were observed between netarsudil or vehicle treated eyes. When comparing efficacy of topical netarsudil BID and topical ripasudil 0.4% administered four times daily from our previous study, dogs receiving ripasudil had significantly less progression than those receiving netarsudil.

The Role of Rho Kinase Inhibitors in Corneal Diseases.

The cornea, as the outermost layer of the eye, plays a crucial role in vision by focusing light onto the retina. Various diseases and injuries can compromise its clarity, leading to impaired vision. This review aims to provide a thorough overview of the pharmacological properties, therapeutic potential and associated risks of Rho-associated protein kinase (ROCK) inhibitors in the management of corneal diseases. The article focuses on four key ROCK inhibitors: Y-27632, fasudil, ripasudil, and netarsudil, providing a comparative examination. Studies supporting the use of ROCK inhibitors highlight their efficacy across diverse corneal conditions. In Fuchs' endothelial corneal dystrophy, studies on the application of Y-27632, ripasudil, and netarsudil demonstrated noteworthy enhancements in corneal clarity, endothelial cell density, and visual acuity. In pseudophakic bullous keratopathy, the injection of Y-27632 together with cultured corneal endothelial cells into the anterior chamber lead to enhanced corneal endothelial cell density and improved visual acuity. Animal models simulating chemical injury to the cornea showed a reduction of neovascularization and epithelial defects after application of fasudil and in a case of iridocorneal endothelial syndrome netarsudil improved corneal edema. Addressing safety considerations, netarsudil and ripasudil, both clinically approved, exhibit adverse events such as conjunctival hyperemia, conjunctival hemorrhage, cornea verticillata, conjunctivitis, and blepharitis. Monitoring patients during treatment becomes crucial to balancing the potential therapeutic benefits with these associated risks. In conclusion, ROCK inhibitors, particularly netarsudil and ripasudil, offer promise in managing corneal diseases. The comparative analysis of their pharmacological properties and studies supporting their efficacy underscore their potential therapeutic significance. However, ongoing research is paramount to comprehensively understand their safety profiles and long-term outcomes in diverse corneal conditions, guiding their optimal application in clinical practice.

Assessment of breast cancer chemotherapy dose reduction in an integrated healthcare delivery system.

PURPOSE: Most cytotoxic drugs are dosed using body surface area (BSA), yet not all cancer patients receive the full BSA-determined dose. Prior work suggests that breast cancer patients who are obese are more likely to experience dose reduction than normal weight patients. However, the factors driving dose reduction remain unclear. METHODS: In 452 women diagnosed with stage I-IIIA primary breast cancer at Kaiser Permanente Northern California, we evaluated the association between obesity and dose reduction, and further explored other factors in relation to dose reduction, including various sociodemographic characteristics, tumor characteristics, and comorbidities. Study participants were a part of the Pathways Study, diagnosed between 2006 and 2013 and treated with cyclophosphamide + doxorubicin, followed by paclitaxel (ACT). Dose reduction was assessed using first cycle dose proportion (FCDP) and average relative dose intensity (ARDI), a metric of dose intensity over the course of chemotherapy. RESULTS: Overall, 8% of participants received a FCDP < 90% and 21.2% had an ARDI < 90%, with dose reduction increasing with body mass index. In adjusted logistic regression models, obese women had 4.1-fold higher odds of receiving an ARDI < 90% than normal weight women (95% CI: 1.9-8.9; p-trend = 0.0006). Increasing age was positively associated with an ADRI < 90%, as was the presence of comorbidity. Dose reduction was less common in later calendar years. CONCLUSION: Results offer insight on factors associated with chemotherapy dosing for a common breast cancer regimen. Larger studies are required to evaluate relevance to other regimens, and further work will be needed to determine whether dose reductions impact outcomes in obese women.

MERCURY-3: a randomized comparison of netarsudil/latanoprost and bimatoprost/timolol in open-angle glaucoma and ocular hypertension.

PURPOSE   : To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda®) with bimatoprost 0.03%/timolol maleate 0.5% (BIM/TIM; Ganfort®) ophthalmic solution in the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT). METHODS: MERCURY-3 was a 6-month prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3. RESULTS: Overall, 430 patients were randomized (NET/LAT, n = 218; BIM/TIM, n = 212), and all received at least one dose of study medication. Efficacy analyses were performed at Month 3 on 388 patients (NET/LAT, n = 184; BIM/TIM, n = 204). NET/LAT demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) through Month 3. Mean diurnal IOP during the study ranged from 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups respectively, with no between-group statistically significant difference. No significant differences were observed in key secondary endpoints. No serious, treatment-related adverse events (AEs) were observed, and AEs were typically mild/moderate in severity. The most common treatment-related AEs were conjunctival hyperemia (NET/LAT, 30.7%; BIM/TIM, 9.0%) and cornea verticillata (NET/LAT, 11.0%; BIM/TIM, 0%). CONCLUSIONS: Once-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT.

Comparison of safety and efficacy of Netarsudil 0.02% and Bimatoprost 0.01% monotherapy and combination therapy in primary open-angle glaucoma and ocular hypertension.

PURPOSE: To study and compare the efficacy and safety profile of Rho-kinase inhibitor (netarsudil 0.02%) and prostaglandin analog (bimatoprost 0.01%) both as monotherapy and in combination. DESIGN: Prospective, randomized, monocentric, open-label clinical trial. METHODS: Patients ≥20 years of age with primary open-angle glaucoma or ocular hypertension (IOP >21 mmHg) were recruited and randomized to receive either netarsudil 0.02%, netarsudil 0.02% + bimatoprost 0.01%, or bimatoprost 0.01% once daily for a period of 12 weeks. IOP and side effects were documented at 4, 8, and 12 weeks. RESULTS: The mean treated IOP ranged 17.51-18.57 mmHg for netarsudil, 15.80-16.46 mmHg for bimatoprost, and 14.00-14.87 mmHg for the combination therapy group. The mean IOP reduction from baseline at 4, 8, and 12 weeks was found to be statistically significant ( P < 0.001) in all three groups. The safety profile of netarsudil/bimatoprost combination was consistent with each constituent individually. The only frequently observed ocular adverse event was conjunctival hyperemia, which was seen mostly in netarsudil and netarsudil + bimatoprost groups ( P < 0.001). CONCLUSION: The IOP-lowering effect of netarsudil 0.02% once daily is non-inferior to bimatoprost 0.01% in patients with POAG and ocular hypertension with acceptable ocular safety, and the combination therapy achieved a higher IOP-lowering effect. This group of medications can be a useful adjunct in patients on maximal therapy.

Stereoselective α-Deuteration of Serine, Cysteine, Selenocysteine, and 2,3-Diaminopropanoic Acid Derivatives.

Efficient methodologies for synthesizing enantiopure α-deuterated derivatives of serine, cysteine, selenocysteine, and 2,3-diaminopropanoic acid have been developed. H/D exchange was achieved by deprotonation of a chiral bicyclic serine equivalent followed by selective deuteration. Additionally, diastereoselective additions of thiols, selenols, and amines to a chiral bicyclic dehydroalanine in deuterated alcohols allowed site-selective deuteration at the Cα atom of cysteine, selenocysteine, and 2,3-diaminopropanoic acid derivatives. A deuterated analogue of carbocysteine, a drug for the treatment of bronchiectasis, was synthesized.

Comparison of Netarsudil/Latanoprost Therapy with Latanoprost Monotherapy for Lowering Intraocular Pressure: A Systematic Review and Meta-analysis.

PURPOSE: Netarsudil is a Rho kinase inhibitor and the first new class of clinically useful ocular hypotensive agents. In this study, we conducted a systematic literature review and meta-analysis to summarize and synthesize the available evidence on the efficacy and safety of fixed-dose combination (FDC) therapy with netarsudil/latanoprost in patients with glaucoma. METHODS: We identified relevant studies in PubMed, Ovid Medline, Embase, and Cochrane Central until April 2021. The quality of the studies and the level of evidence were assessed using the Risk of Bias tool. Efficacy was measured as the mean difference in reducing intraocular pressure (IOP), and safety was assessed by the risk of conjunctival hyperemia (CH) due to FDC therapy, netarsudil monotherapy, or latanoprost monotherapy. RESULTS: Four studies met the predefined eligibility criteria and were included in the meta-analysis. The mean difference in the reduction in IOP after 2 weeks and 4 to 6 weeks of drug administration was -2.41 mmHg (95% confidence interval [CI], -2.95 to -1.87) and -1.77 mmHg (95% CI, -2.31 to -1.87), respectively, in patients receiving FDC therapy versus those receiving latanoprost monotherapy. On the other hand, latanoprost monotherapy had a greater effect in reducing IOP than netarsudil monotherapy after 4 to 6 weeks of administration (mean difference, 0.95 mmHg; 95% CI, 0.43 to 1.47). The risk of CH was significantly higher with both FDC therapy and netarsudil monotherapy compared to latanoprost monotherapy in week 12, where the relative ratio was 3.01 (95% CI, 1.95 to 4.66) and 2.33 (95% CI, 1.54 to 3.54), each. CONCLUSIONS: Netarsudil/latanoprost FDC therapy has a significantly greater effect on reducing IOP than latanoprost alone. The symptoms of CH were mostly mild, and only a few glaucoma patients discontinued the medication owing to CH in earlier clinical trials. Therefore, it would be beneficial to consider the administration of netarsudil/latanoprost FDC therapy in patients with glaucoma.

Pragmatic adjunctive usage of netarsudil: A retrospective chart review from a tertiary care center.

Purpose: This retrospective chart review of netarsudil (Rhopressa) characterizes intra-ocular pressure (IOP) reduction, drug tolerance, drug cost, and compliance in a tertiary university Midwest clinic in a variety of glaucoma diagnoses on patients prescribed netarsudil 01/2017 to 5/2020. Methods: Patient demographics, primary diagnosis, indication for medication, prescription date, prescription fill status, duration of use, discontinuation reason, and number of IOP-lowering medications were noted. Confounding medication changes were excluded from IOP analysis. The IOP difference between the first visit after starting netarsudil and the baseline (mean before starting netarsudil on the stable medication regimen) was calculated. Results: A total of 133 patients were prescribed netarsudil (age 69 ± 20 years, 59% females, 79% white, 86% primary glaucoma) as adjunct glaucoma medication (mean medications 3.2 ± 0.9). Indications were lowering IOP (mean baseline IOP 20.0 ± 6 mmHg) and drug regimen simplification. Prescription was not filled by 22/133 subjects because of the cost (68%) and the need for surgery (23%). No demographic factors were associated with prescription fill status. A total of 101 eyes of 76 patients were used for IOP analysis. The mean change in IOP was -0.8 ± 6.4 mmHg, (IOP decrease in 67%, increase or no change in 33% eyes). Netarsudil was discontinued in 52% (50/96) patients; the reasons include surgery for IOP control (42%), allergies (30%), cost (14%), and paradoxical rise in IOP (12%). Conclusion: Netarsudil was used as adjunct third or fourth line medication at a glaucoma practice in Midwestern USA. 17% of prescriptions went unfilled; netarsudil was discontinued in 52% of patients. IOP response was variable in this population with severe complex glaucoma.

Reticular epithelial edema after penetrating keratoplasty in a patient taking netarsudil.

Netarsudil is a relatively new medication for the treatment of primary open-angle glaucoma and ocular hypertension. It has been associated with red eyes and burning after instillation. Reticular epitheliopathy is a relatively rare complication of netarsudil that has been described in patients with preexisting corneal edema. We report the case of a healthy 76-year-old woman who developed reticular epitheliopathy after full-thickness penetrating keratoplasty that completely resolved following discontinuation of the medication. In cases where netarsudil is initiated for treatment of glaucoma or, off-label, endothelial dysfunction, reticular epithelial edema should be considered in patients complaining of a decline in vision and severe pain.

Neurotoxin (N-Oxalyl-L-α,ß-Diamino Propionic Acid) Content in Different Plant Parts of Grass Pea (Lathyrus sativus L.) Spanning Seedling to Maturity Stage: Does It Increase over Time?

ODAP (N-oxalyl-L-2,3-diaminopropionic acid) is present in the seeds of grass pea. In this study, variation of total ODAP accumulation in leaves throughout the crop growth starting from 40 days after sowing to maturity, and the distribution pattern of ODAP in different plant parts including the seeds at the mature stage was analyzed. Five grass pea accessions were evaluated for two subsequent growing seasons in one location of ICARDA, Aleppo (Syria). The results found that the rate of accumulation of total ODAP varied during plant development. Increased rates of synthesis were noticed in young leaves of grass pea. The highest total ODAP content in leaves was noted in the early growth stage (40-50 days after sowing). Mean total ODAP content in leaves ranged from 0.17 to 0.96 percent during 2010-2011 and from 0.19 to 1.28 percent during 2011-2012. During maturity, the total ODAP content was lowest in the seeds than in leaves, stems, pod cover, seed coat, and cotyledons. The ranges of total ODAP content were 0.13 (seed)-0.34 (stem), 0.20 (seed)-1.01 (leaf), 0.22 (seed)-0.62 (leaf), 0.21 (seed)-0.66 (leaf), and 0.21 (seed)-0.78 (leaf) percent in B387, B222, B390, Bio-520, and B587 accessions, respectively, during maturity. The results indicated that the rate of accumulation and synthesis of total ODAP varied during the plant lifespan. The lowest total ODAP content of leaves was observed after 130 days of sowing. The lower total ODAP content after the early vegetative stage of grass pea plants makes them suitable as a feed.

Case Report: Topical Netarsudil in the Treatment of a Neurotrophic Corneal Ulcer.

SIGNIFICANCE: Rho-associated kinase inhibitors have been used in glaucoma management for reducing intraocular pressure. Their role in treating corneal endothelial damage and promoting corneal epithelial healing has also been reported. Presented is a case report demonstrating healing of a previously nonresponsive neurotrophic ulcer with addition of the Rho-associated kinase inhibitor, netarsudil. PURPOSE: Early in vitro -based research on corneal application of Rho-associated kinase inhibitors has shown these molecules to be beneficial to corneal epithelial wound healing. The presented case supports their use in epithelial disease. It is the author's hope that this will inspire further investigation. CASE REPORT: Presented here is a case report describing the use of netarsudil, a Rho-associated kinase inhibitor in the management of a neurotrophic corneal ulcer that was nonresponsive to frontline therapy. The application of netarsudil was followed by rapid healing of the defect, although a concomitant increase in mucous production was also noted. CONCLUSIONS: This case supports the use of netarsudil as an agonist of epithelial healing, although further research is needed.

Response to netarsudil in goniotomy-treated eyes and goniotomy-naïve eyes: a pilot study.

PURPOSE: To compare the intraocular pressure (IOP)-lowering effects of netarsudil on goniotomy-treated eyes versus goniotomy-naïve control eyes. METHODS: Retrospective cohort study of 70 eyes from 49 adult glaucoma patients treated with netarsudil. Thirty-five eyes received sectoral goniotomy using Kahook Dual Blade (KDB) combined with cataract surgery with minimum of 3 months prior to netarsudil treatment. Thirty-five eyes in the control cohort received only cataract surgery prior to netarsudil. Primary outcome was treatment success, defined as ≥ 20% decrease in IOP at minimum 1 month follow-up. Secondary outcome measures included percent of IOP reduction, adverse effects of medication, medication discontinuation rate, and relationship between KDB goniotomy response and netarsudil response. RESULTS: Eighty-three percent of KDB-treated eyes achieved netarsudil treatment success compared to 54% of control eyes (P = .012). IOP reduction was 30.3 ± 16.2% (IQR 21-38%) in KDB-treated eyes and 19.4 ± 12.4% (IQR 9.2-30.8) in control eyes (P = .007). History of prior KDB increased the likelihood of success to netarsudil treatment compared to eyes without prior KDB, regardless of surgical response to KDB (odds ratio 4.51, 95% CI 1.34-15.14, P = .015). The overall rate of adverse effects of netarsudil was 42%, most commonly reported as conjunctival hyperemia, allergy, and blurred vision. CONCLUSIONS: Netarsudil had a greater IOP-lowering effect in eyes treated with prior goniotomy and may serve as a promising adjunctive ocular hypotensive agent to further reduce IOP in eyes with prior goniotomy.

Punctal Stenosis Associated with Topical Netarsudil Use.

PURPOSE: To report a series of patients who developed punctal stenosis secondary to the use of topical netarsudil 0.02% for treatment of glaucoma. DESIGN: Case series. PARTICIPANTS: Patients using topical netarsudil for management of glaucoma and noted to have punctal stenosis ipsilateral to the eye(s) being treated with netarsudil were included. METHODS: Each enrolled patient's chart was reviewed, and alternative causes of punctal stenosis were sought. Photographs were obtained to document punctal stenosis for some patients. MAIN OUTCOME MEASURES: Presence of punctal stenosis after topical netarsudil use and resolution of punctal stenosis after cessation of therapy. RESULTS: Sixteen patients had punctal stenosis; 13 developed unilateral punctal stenosis while using netarsudil unilaterally, and 3 patients developed bilateral punctal stenosis with bilateral use. Time from initiation of netarsudil to recognition of symptoms or documentation of punctal stenosis ranged from 2 to 35 months (median, 12; mean, 14.0 ± 8.7 months). Thirteen patients endorsed tearing, but 2 had no symptoms. Ectropion was seen in 1 eye. Corneal verticillata was noted in 14 patients (87.5%). In 8 cases, netarsudil was discontinued, and the punctal stenosis was reversed, with resolution of associated symptoms. CONCLUSIONS: Netarsudil use can lead to the development of reversible punctal stenosis. This inflammation-mediated stenosis may cause tearing and associated symptoms and may be of sufficient severity to necessitate discontinuation of treatment. In this case series, all patients who discontinued treatment had reversal of their punctal stenosis and associated symptoms.

Axonal Protection by Netarsudil, a ROCK Inhibitor, Is Linked to an AMPK-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration.

Purpose: Netarsudil, a Rho kinase inhibitor with norepinephrine transport inhibitory effect, lowers intraocular pressure, however, its effect on axon damage remains to be elucidated. The aim of the current study was to investigate the effect of netarsudil on TNF-induced axon loss and to examine whether it affects phosphorylated-AMP-activated kinase (p-AMPK) and autophagy in the optic nerve. Methods: Intravitreal administration of TNF or TNF with netarsudil was carried out on rats and quantification of axon number was determined. Electron microscopy determined autophagosome numbers. Localization of p-AMPK expression was examined by immunohistochemistry. The changes in p62, LC3-II, and p-AMPK levels were estimated in the optic nerve by immunoblot analysis. The effect of an AMPK activator A769662 or an AMPK inhibitor dorsomorphin on axon number was evaluated. Results: Morphometric analysis revealed apparent protection by netarsudil against TNF-induced axon degeneration. Netarsudil increased autophagosome numbers inside axons. Netarsudil treatment significantly upregulated optic nerve LC3-II levels in both the TNF-treated eyes and the control eyes. Increased p62 protein level induced by TNF was significantly ameliorated by netarsudil. The netarsudil administration alone lessened p62 levels. Netarsudil significantly upregulated the optic nerve p-AMPK levels. A769662 exhibited obvious axonal protection against TNF-induced damage. A769662 treatment upregulated LC3-II levels and the increment of p62 level induced by TNF was significantly ameliorated by A769662. Immunohistochemical analysis revealed that p-AMPK is present in axons. Netarsudil-mediated axonal protection was significantly suppressed by dorsomorphin administration. Conclusions: Netarsudil upregulated p-AMPK and autophagy. Netarsudil-mediated axonal protection may be associated with upregulated p-AMPK.

Case Report: Intracorneal Hemorrhages Seen with Scleral Contact Lens Wear and Netarsudil Therapy.

SIGNIFICANCE: Intracorneal hemorrhages are a rare finding generally associated with surgery or trauma. There is no consensus on preferred management except eliminating or addressing the causative mechanism in hopes of reducing the risk of corneal haze or scarring. PURPOSE: This case highlights a rare adverse outcome of intracorneal hemorrhages occurring after recent initiation of netarsudil, possibly exacerbated by scleral contact lens wear in a patient with open-angle glaucoma and limbal stem cell deficiency. CASE REPORT: A 77-year-old man using scleral contact lenses for therapeutic management of limbal stem cell deficiency started netarsudil for open-angle glaucoma. During an annual follow-up to adjust his scleral contact lenses, the patient developed peripheral intracorneal hemorrhages bilaterally. The intracorneal hemorrhages resolved over the course of 10 weeks after minor adjustments were made to the scleral contact lens fit and netasurdil was discontinued. Visual acuity and intraocular pressure remained stable throughout. CONCLUSIONS: There are few reports of intracorneal hemorrhages associated with scleral contact lens use and even fewer associated with the use of netarsudil. This case proposes several possible causes of the intracorneal hemorrhages, including topical rho-associated kinase inhibitors, contact lens wear, and trauma. Further studies are needed to determine if netarsudil is associated with intracorneal hemorrhages, to understand the sequelae of intracorneal hemorrhages in netarsudil therapy, and to recommend management when intracorneal hemorrhages manifest with netarsudil use.

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.

Anterior Subcapsular Cataract Formation With Long-term Topical Netarsudil Treatment for Glaucoma.

PURPOSE: The purpose of this study was to describe anterior subcapsular cataract development in patients on long-term topical netarsudil use. PATIENTS AND METHODS: This clinical observational study summarizes a similar cataract pattern demonstrated in a series of patients from a single physician practice and a university-based outpatient clinic during their routine clinical follow-up visits from October 2020 to August 2021. All patients have been using topical netarsudil once daily for at least 15 months. No anterior capsular changes have been observed in any patient at the time when netarsudil was initiated. RESULTS: Five eyes from 4 patients between the ages of 41 and 61 and 1 eye from a patient aged 84 were found to develop anterior subcapsular opacities 15 to 37 months after beginning netarsudil. These cataracts were overall small, 1 to 3 mm, round, oval or ring-shaped, central or paracentral with mild density. No other risk factors for cataract development apart from age were found in these patients. CONCLUSION: Patients on long-term netarsudil should be monitored for potential development of anterior subcapsular cataracts.

Benfuracarb inhibits body growth and causes oxidative stress in zebrafish (Danio rerio).

Benfuracarb (BEN), a broad-spectrum carbamate insecticide used for crop protection, is considered toxic to humans and aquatic organisms. However, the potential risk level of BEN to aquatic organisms is still unclear. In this study, we exposed zebrafish embryos to BEN (0.08, 0.49, and 0.90 mg/L) from 3 to 96 hours post-fertilization (hpf). The results showed that BEN caused shorter body length in zebrafish larvae. The activity of superoxide dismutase (SOD) was significantly increased after BEN exposure. Furthermore, the transcription levels of marker genes associated with early embryonic development (myoD, nkx2.4b, myh6, and gh) were disrupted after BEN treatment. Taken together, the data indicate that BEN possesses developmental toxicity to zebrafish. The results provide a valuable reference for assessing BEN's potentially harmful effects on aquatic ecosystems.

Role of abscisic acid in modulating drought acclimation, agronomic characteristics and ß-N-oxalyl-L-α,ß-diaminopropionic acid (ß-ODAP) accumulation in grass pea (Lathyrus sativus L.).

BACKGROUND: ß-N-oxalyl-l-α,ß-diaminopropionic acid (ß-ODAP) is a physiological indicator in response to drying soil. However, how abscisic acid (ABA) modulates ß-ODAP accumulation and its related agronomic characteristics in drought stressed grass pea (Lathyrus sativus L.) continue to be unclear. The present study aimed to evaluate the effects of ABA addition on drought tolerance, agronomic characteristics and ß-ODAP content in grass pea under drought stress. RESULTS: Exogenous ABA significantly promoted ABA levels by 19.3% and 18.3% under moderate and severe drought stress, respectively, compared to CK (without ABA, used as control check treatment). ABA addition activated earlier trigger of non-hydraulic root-sourced signal at 69.1% field capacity (FC) (65.5% FC in CK) and accordingly prolonged its operation period to 45.6% FC (49.0% FC in CK). This phenomenon was mechanically associated with the physiological mediation of ABA, where its addition significantly promoted the activities of leaf superoxide dismutase, catalase and peroxidase enzymes and the biosynthesis of leaf proline, simultaneously lowering the accumulation of malondialdehyde and hydrogen peroxide under moderate and severe stresses. Interestingly, ABA application significantly increased seed ß-ODAP content by 21.7% and 21.3% under moderate and severe drought stress, but did not change leaf ß-ODAP content. Furthermore, ABA application produced similar shoot biomass and grain yield as control groups. CONCLUSION: Exogenous ABA improved the drought adaptability of grass pea and promoted the synthesis of ß-ODAP in seeds but not in leaves. Our findings provide novel insights into the agronomic role of ABA in relation to ß-ODAP enrichment in grass pea subjected to drought stress. © 2021 Society of Chemical Industry.

Experience with netarsudil 0.02% and latanoprostene bunod 0.024% as adjunctive therapy for glaucoma.

PURPOSE: To assess the effectiveness and safety of adjunctive topical netarsudil 0.02% and latanoprostene bunod 0.024% in patients with glaucoma. METHODS: A retrospective, multi-center, cohort study of patients with glaucoma treated with netarsudil 0.02% or latanoprostene bunod from five tertiary care centers. Inclusion criteria included patients with glaucoma treated with either medication as adjunctive therapy. Outcomes included mean absolute intraocular pressure (IOP) reduction and relative IOP reduction from baseline. Adverse reactions and reasons for discontinuation were reported. One-way analysis of variance, Kruskal-Wallis rank sum test, and Mann Whitney U test compared the outcomes. RESULTS: A total of 95 eyes (95 patients) on netarsudil and 41 eyes (41 patients) on latanoprostene bunod were analyzed. Mean duration of use was 54.3 ± 28 days for netarsudil and 82.9 ± 51.2 days for latanoprostene bunod. At the final visit, mean IOP reduction was 3.9 ± 4.6 mmHg (17.5 ± 6.0%) (p < 0.0001) with netarsudil and 2.9 ± 3.7 mmHg (13.6 ± 16.3%) (p < 0.0001) with latanoprostene bunod. IOP lowering did not depend on baseline number of IOP-lowering medications. The most common reason for discontinuation was non-effectiveness in both groups. CONCLUSION: Similar to monotherapy, netarsudil and latanoprostene bunod demonstrated efficacy in lowering IOP when used as adjunctive therapy.